EP1812440B1 - Pyrazolo[1,5-a]pyrimidines useful as inhibitors of protein kinases - Google Patents

Pyrazolo[1,5-a]pyrimidines useful as inhibitors of protein kinases Download PDF

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EP1812440B1
EP1812440B1 EP05816516A EP05816516A EP1812440B1 EP 1812440 B1 EP1812440 B1 EP 1812440B1 EP 05816516 A EP05816516 A EP 05816516A EP 05816516 A EP05816516 A EP 05816516A EP 1812440 B1 EP1812440 B1 EP 1812440B1
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compound according
alkyl
aliphatic
optionally substituted
membered heterocyclyl
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French (fr)
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EP1812440A1 (en
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Juan-Miguel Jimenez
Ronald Knegtel
Jean-Damien Charrier
Dean Stamos
Pan Li
Jon R. Come
Alex Aronov
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Definitions

  • the present invention relates to compounds useful as inhibitors of protein kinases, particularly Tec family kinases, Aurora kinases and c-Met.
  • the invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and the use of the compositions in the manufacture of medicaments for the treatment of various disorders.
  • the invention also provides processes for preparing the compounds of the invention.
  • the Tec family of non-receptor tyrosine kinases plays a central role in signalling through antigen-receptors such as the TCR, BCR and Fc ⁇ receptors and are essential for T cell activation. Deletion of Itk in mice results in reduced T cell receptor (TCR)-induced proliferation and secretion of the cytokines IL-2, IL-4, IL-5, IL-10 and IFN- ⁇ . Itk has been implicated in allergic asthma and atopic dermatitis.
  • TCR T cell receptor
  • Tec family kinases are also essential for B cell development and activation. Patients with mutations in Btk have a profound block in B cell development, resulting in the almost complete absence of B lymphocytes and plasma cells, severely reduced Ig levels and a profound inhibition of humoral response to recall antigens. Btk deletion in mice has a profound effect on B cell proliferation induced by anti-IgM, and inhibits immune responses to thymus-independent type II antigens.
  • Tec kinases also play a role in mast cell activation through the high-affinity IgE receptor (Fc ⁇ RI). Itk and Btk are expressed in mast cells and are activated by Fc ⁇ RI cross-linking. Btk deficient murine mast cells have reduced degranulation and decreased production of proinflammatory cytokines following Fc ⁇ RI cross-linlting. Btk deficiency also results in a decrease of macrophage effector functions.
  • Fc ⁇ RI high-affinity IgE receptor
  • Aurora proteins are a family of three highly related serine/threonine kinases (termed Aurora-A, -B and -C) that are essential for a cell's progression through the mitotic phase of the cell cycle. Specifically Aurora-A plays a crucial role in centrosome maturation and segregation, formation of the mitotic spindle, and faithful segregation of chromosomes.
  • Aurora-B is a chromosomal passenger protein that plays a central role in regulating the alignment of chromosomes on the meta-phase plate, in the spindle assembly checkpoint, and also in the correct completion of cytokinesis.
  • Aurora-A Aurora-2
  • Aurora-B Aurora-1
  • Aurora-C Adenocarcinomas
  • siRNA dominant negative or neutralizing antibodies
  • c-Met receptor tyrosine kinase is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis.
  • the various cancers in which c-Met is implicated include, but are not limited to, gastric adenocarcinoma, renal cancer, small cell lung carcinoma, colorectal cancer, colon cancer, prostate cancer, brain cancer, liver cancer, pancreatic cancer, and breast cancer.
  • c-Met is also implicated in atherosclerosis, lung fibrosis, allergic disorders, autoimmune disorders, and conditions associated with organ transplantation.
  • WO 98/54093 WO 2004/052315 A2 and WO 00/53605 describe compounds useful to treat tyrosine kinase-dependent diseases and conditions.
  • WO 02/066481 A1 describe pyrimidine derivatives for inhibition of cell proliferation.
  • compounds of this invention are effective as inhibitors of protein kinases.
  • these compounds are effective as inhibitors Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases, Aurora family kinases and/or c-Met.
  • Tec family e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk
  • Aurora family kinases e.g., Aurora family kinases and/or c-Met.
  • These compounds and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions.
  • the compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
  • the invention provides a compound selected from one of the following:
  • the invention provides a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • the composition further comprises an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • AIDS Acquired Immunodeficiency Syndrome
  • the invention also provides methods of inhibiting Tec family kinase activity in a biological sample in vitro comprising contacting said biological sample with, a compound of the invention or a composition comprising said compound.
  • the method comprises inhibiting Itk activity.
  • the invention also provides the use of a compound of the present invention or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of a disease of condition selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease.
  • the treatment comprises administering to said patient an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS), wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
  • an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS), wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
  • the disease or disorder is asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas,
  • R 4 is H
  • R 3 is other than H.
  • R 4 is H and R 3 is other than H.
  • Z is a bond.
  • R 1 is H.
  • R is In further embodiments, Q is N or O. In further embodiments, R 2a is OR 5 , N(R 5 ) 2 , or 5-8 membered heterocyclyl. In further embodiments, the 5-8 membered heterocyclyl contains 1-2 nitrogen atoms.
  • the 5-8 membered heterocyclyl is optionally substituted with 0-4 occurrences of C 1-6 aliphatic, C 1-4 haloalkyl, CN, halo, OH, O-(C 1-6 aliphatic), NH 2 , NH(C 1-6 aliphatic), N(C 1-6 aliphatic) 2 , benzyl, -CH 2 -(pyridyl), or -CH 2 -pyrrolidinyl.
  • R 2a is N(R 5 ) 2 .
  • R 5 is H or an optionally substituted group selected from 5-8 membered heterocyclyl, -(C 1-6 alkyl)-(5-8 membered heterocyclyl), 5-6 membered heteroaryl -(C 1-6 alkyl)-(5-6 membered heteroaryl), phenyl, -(C 1-6 alkyl)-(phenyl), C 3-10 cycloaliphatic, -(C 1-6 alkyl)-(C 3-10 cycloaliphatic) and C 1-6 aliphatic wherein up to three methylene unit of the aliphatic chain are optionally and independently replaced by -NR"-, -O-, or -S- in a chemically stable arrangement.
  • R 5 is H or an optionally substituted group selected from pyrrolidinyl, piperidinyl, piperazinyl, -CH 2 -(5-6 membered heteroaryl), phenyl, benzyl, and C 1-6 aliphatic wherein up to one methylene unit of the aliphatic chain is optionally and independently replaced by -NR"-, -O-, or -Sin a chemically stable arrangement.
  • J R5 is halo, CN, C 1-4 haloalkyl, or an optionally substituted group selected from phenyl, benzyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, CH 2 -(5-6 membered heteroaryl), CH 2 -(5-8 membered heterocyclyl), and C 1-6 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NR"-, -O-, -S-, -C(O)-, -SO-, or -SO 2 -, in a chemically stable arrangement.
  • J R5 is halo, CN, phenyl, benzyl, CH 2 -(pyridyl), CH 2 -(pyrrolidinyl), or C 1-6 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by - NR"-, -O-, or -S-.
  • R is Y.
  • Y is an optionally substituted 5-10 membered heteroaryl or heterocyclyl.
  • Y is an optionally substituted 5-6 membered heteroaryl or 5-8 membered heterocyclyl.
  • Y is a pyridine ring optionally substituted with 0-4 J Y .
  • Y is a 2-pyridine ring optionally substituted with 0-4 J Y .
  • J Y is halo, CN, NO 2 , C 1-6 haloaliphatic, phenyl, benzyl, 5-6 membered heteroaryl, C 1-6 alkyl-(5-6 membered heteroaryl), C 3-10 cycloaliphatic, (C 1-6 alkyl)-(C 3-10 cycloaliphatic), 5-8 membered heterocyclyl, C 1-6 alkyl-(5-8 membered heterocyclyl), or C 1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NR-, -O-, -S-, -C(O)-, -SO-, or -SO 2 - in a chemically stable arrangement.
  • J Y is halo, CN, NO 2 , CF 3 , C 1-6 aliphatic, phenyl, benzyl, -O-benzyl, piperidinyl, pyrrolidinyl, -NR(C 1-6 alkyl), -O(C 1-6 alkyl), -S(C 1-6 alkyl), OH, SH, or NH 2 .
  • R 3 and R 4 are each independently U m -V.
  • V is H, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloaliphatic, or 5-10 membered heterocyclyl optionally substituted with 0-4 R 8 .
  • V is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl, or 5-8 membered heterocyclyl.
  • V is an optionally substituted group selected from phenyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In still further embodiments, V is optionally substituted phenyl.
  • R 3 is U m -V; m is 1, and U is C 1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by -C(O)-, -C(O)NR 5 -, or -C(O)O-.
  • U is -C(O)NR 5 -.
  • V is optionally substituted phenyl or optionally substituted pyridyl.
  • R 3 is U m -V, m is zero and V is aryl or heteroaryl.
  • R 8 is halogen, C 1-4 haloalkyl, phenyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, -OR 6 , -N(R 6 ) 2 , -SR 6 , NO 2 , CN, - COOR 6 , -C(O)N(R 6 ) 2 , -SO 2 R 6 , -SO 2 N(R 6 ) 2 , -NR 6 C(O)R 6 , -C(O)R 6 , -NR 6 SO 2 -R 6 , -C(O)NR 6 N(R 6 ) 2 , or C 1-12 aliphatic, wherein up to three methylene units of the aliphatic chain can be optionally interrupted with -C(O)R 6 , -C(O)O-, -OC(O)-, -C(O)-, -C(O)N(R 6 )-,
  • R 8 is -OR 6 , -N(R 6 ) 2 , C(O)R 6 , -C(O)N(R 6 ) 2 , or 5-7 membered heterocyclyl. In still further embodiments, R 8 is -C(O)N(R 6 ) 2 or C(O)R 6 .
  • R 6 is H or an optionally substituted group selected from 5-8 membered heterocyclyl, -(C 1-6 alkyl)-(5-8 membered heterocyclyl), benzyl, -(C 1-6 alkyl)-(5-8 membered heteroaryl), and C 1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement.
  • R 6 is H or an optionally substituted group selected from a 5-8 membered heterocyclyl and C 1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement.
  • J R6 is selected from C 1-6 alkyl, halo, CN, OH, -O(C 1-6 alkyl), NH 2 , -N(C 1-6 alkyl), and -N(C 1-6 alkyl) 2 .
  • J" is selected from C 1-6 aliphatic, halo, CN, OH, -O(C 1-6 alkyl), NH 2 , -N(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C(O)OH, -C(O)O(C 1-6 alkyl), 5-6 membered heteroaryl, -CH 2 -(5-6 membered heteroaryl), 5-6 membered heterocyclyl, -CH 2 -(5-6 membered heterocyclyl), and C 1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement.
  • Z is a bond and R is selected from
  • R is selected from
  • R is
  • J Y is selected from -X-(C 6-10 aryl), -X-(5-10 membered heteroaryl), -X-(C 3-10 cycloaliphatic), -X-(5-10 membered heterocyclyl), or X.
  • X is C 1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by NR"-, -O-, -S-, -C(O)-, -SO-, or -SO 2 -.
  • X is C 1-12 aliphatic wherein up to one methylene unit is optionally and independently replaced by -NR"-.
  • at least one NR"- is directly attached to R.
  • J Y is an optionally substituted group selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloaliphatic, and 5-10 membered heterocyclyl.
  • J Y is halo, CN, NO 2 , CF 3 , OR", SR", or N(R") 2 .
  • R is substituted with 2 occurrences of J Y wherein one J Y is selected from -X-(C 6-10 aryl), -X-(5-10 membered heteroaryl), -X-(C 3-10 cycloaliphatic), -X-(5-10 membered heterocyclyl), or X and the other J Y is selected from H, halo, CN, NO 2 , CF 3 , OR", SR", N(R") 2 , C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloaliphatic, or 5-10 membered heterocyclyl.
  • R is substituted with 2 occurrences of J Y wherein one J Y is selected from X and the other J Y is selected from H, halo, CN, NO 2 , CF 3 , OR", SR", or N(R") 2 .
  • the invention provides a compound of formula II: or a pharmaceutically accepted salt thereof, wherein Ring A is Y.
  • R 4 is H
  • R 3 is other than H.
  • R 4 is H and R 3 is other than H.
  • the invention provides a compound of formula III: or a pharmaceutically accepted salt thereof, wherein R 3 is halogen, C 1-6 aliphatic, C 1-6 alkoxy, N(R 5 ) 2 , CN, NO 2 , or U m -V; Ring A is a 5-8 membered monocyclic heteroaryl ring.
  • Ring A has the formula
  • Ring A has a formula selected from the group consisting of:
  • the invention provides a compound of formula IV: wherein each of Z 1 and Z 2 is CH or N and R 3 is as defined for formula III.
  • Z 2 is CH. In some embodiments, Z 1 is N or CH. In further embodiments, Z 1 is N and Z 2 is CH. In further embodiments, Z 1 and Z 2 are both CH.
  • R 3 is C 1-6 aliphatic. In further embodiments, R 3 is C 1-3 alkyl.
  • J Y is optionally substituted -N(R 9 ) 2 . In further embodiments, J Y is optionally substituted -NHR 9 . In further embodiments, J Y is optionally substituted-N(R 9 ) 2 , wherein said two R 9 form an optionally substituted 5-8 membered heterocyclyl.
  • the invention provides a compound selected from Table 5.
  • the invention provides a composition comprising a compound of formulae I' , II, III or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • the composition comprises an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • AIDS Acquired Immunodeficiency Syndrome
  • the invention provides a method of inhibiting Tec family kinase activity in a biological sample in vitro, which method comprises contacting said biological sample with, a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound. In further embodiments, the method comprises inhibiting Itk activity.
  • the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of a disease of condition in a patient in need thereof, wherein said disease or condition is selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease.
  • the treatment comprises administering to said patient an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS), wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
  • an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS), wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
  • the disease or disorder to be treated is asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythe
  • the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for inhibiting c-Met kinase activity in a patient or a biological sample.
  • the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of a cancer in a patient in need thereof.
  • the treatment further comprises administering to said patient a chemotherapeutic-agent, wherein chemotherapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
  • the cancer is renal cancer. In other embodiments, the cancer is selected from a glioblastoma, a gastric carcinoma or a cancer selected from colon, breast, prostate, brain, liver, pancreatic or lung cancer. In further embodiments, the cancer is gastric carcinoma. In other embodiments, the cancer is glioblastoma or a cancer selected from breast, colon or liver.
  • the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for inhibiting or reducing the severity of tumor metastasis in a patient in need thereof.
  • the invention provides a method of inhibiting Aurora kinase activity in a biological sample in vitro, which method comprises contacting said biological sample with, a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.
  • the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof.
  • a compound of formulae I', II, III or IV or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof.
  • compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • a C 1-3 alkyl chain optionally interrupted with -O- can form -OCH 2 CH 3 , -CH 2 -OCH 3 , or CH 2 CH 2 OH.
  • the terminal groups are bonded to hydrogen on the terminal side.
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” "cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-20 aliphatic carbon atoms.
  • aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms.
  • cycloaliphatic refers to a monocyclic C 3 -C 8 hydrocarbon or bicyclic C 8 -C 12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • heteroaliphatic means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.
  • heterocycle means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom.
  • the "heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2 H -pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated means that a moiety has one or more units of unsaturation.
  • alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.
  • haloalkyl means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
  • Optional substituents on the aliphatic group of R° are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(haloC 1-4 aliphatic), or haloC 1-4 aliphatic, wherein each of the foregoing C 1-4 aliphatic groups of R° is unsubstituted.
  • Optional substituents on the aliphatic group of R * are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R * is unsubstituted.
  • Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R + is unsubstituted.
  • alkylidene chain refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule, wherein one or more methylene units may optionally and independently be replaced with a group including, but not limited to, CO, CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, O, S; or NR.
  • two independent occurrences of R° are taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Exemplary rings that are formed when two independent occurrences of R° (or R + , or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°) 2 , where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of OR° these two occurrences of R° are taken together with the oxygen atoms to
  • a bond drawn from a substituent to the center of one ring within a multiple-ring system represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system.
  • Figure a represents possible substitution in any of the positions shown in Figure b.
  • each substituent only represents substitution on the ring to which it is attached.
  • Y is an optionally substituent for ring A only
  • X is an optional substituent for ring B only.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • the compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general scheme below, and the preparative examples that follow.
  • Reagents and conditions (a) i) LDA, toluene, ii) o -ClC 4 H 6 CH 2 SCN, toluene, 2 hours; (b) N 2 H 4 .H 2 O, EtOH, reflux, 16 hours.
  • Scheme I above shows a general synthetic route that is used for preparing the compounds 3 of this invention when R and Z are as described herein.
  • Intermediates 2 may be prepared by methods substantially similar to those described in the literature by Davis and Cava J. Org. Chem. 1983, 48, 2774 . Cyclisation of the malononitrile 2 with hydrazine hydrate furnishes the desired diamino-pyrazoles 3 .
  • Reagents and conditions (a) EtOH (in the case of 4 ), i PrOH (in the case of 5 ), AcOH cat. , microwave irradiation, 180°C, 15 minutes.
  • Scheme II above shows a general synthetic route that is used for preparing the compounds 6 of this invention when Z, R and R 3 are as described herein.
  • Pyrazolo[1,5-a]pyrimidines 6 are prepared by microwave assisted cyclisation of diamino-pyrazoles 3 with either a commercially available malonaldehyde 4 or its equivalent 5 .
  • Derivative 5 may be prepared by methods described by Coppola, et al, J. Het. Chem. 1974, 44, 51 .
  • Table 1 below depicts exemplary compounds prepared according to the general methods described in Schemes I and II.
  • Reagents and conditions (a) EtOH, AcOH cat. , reflux, 3 hours; (b) ArB(OH) 2 , Pd(dppf) 2 Cl 2 , 2M Na 2 CO 3 , microwave irradiation, 120°C, 20 minutes.
  • Scheme III above shows a general synthetic route that has been used for preparing compounds 9 of this invention when Z, R and Ar are as described herein.
  • Pyrazolo[1,5-a]pyrimidines 8 are prepared by cyclisation of diamino-pyrazoles 3 with the commercially available 2-bromo-malonaldehyde 7 .
  • the formation of the biaryl link derivatives 9 is achieved by treating bromides 8 with the desired boronic acid derivative in the presence of palladium(0) as a catalyst by using the microwave-assisted Suzuki coupling methods that are well known in the art.
  • the reaction is amenable to a variety of substituted aryl or heteroaryl boronic acids.
  • Reagents and conditions (a) DMF, 160°C, 10 hours; (b) DDQ, 1,4-dioxane, reflux, 2-3 hours.
  • Scheme IV above shows a general synthetic route that has been used for preparing compounds 12 of this invention when Z, R and R 4 are as described herein.
  • the cyclisation of diamino-pyrazoles 3 in presence of ⁇ -dimethylaminoketones 10 has been achieved by methods substantially similar to those described in the literature by Elnagdi and Erian Bull. Chem. Soc. Jpn 1990, 63, 1854 .
  • the reaction is amenable to a variety of diamino-pyrazoles 3 and ⁇ -dimethylaminoketones 10.
  • Intermediates 11 are oxidized with DDQ according to step (b) of Scheme IV.
  • Reagents and conditions (a) AcOH, reflux; (b) i) Protection conditions, ii) POCl 3 , 90°C; (c) i) H 2 , Pd/C, NaOAc, EtOH, ii) Deprotection conditions.
  • Scheme V above shows a general synthetic route that has been used for preparing compounds 16 of this invention when Z, R, R 3 and R 4 are as described herein.
  • Intermediate 14 may be prepared by methods described by Sofon, et al, Pharmazie 1994, 49, 482 and by Ram, et al, Indian J. Chem. Sect. B 1995, 34, 514 .
  • derivatives 15 are obtained by a method well known to one of skill in the art.
  • chloro derivatives 15 are reduced according to Scheme V step (c) i), and the amine is deprotected to afford compounds of structure 16.
  • Reagents and conditions (a) 1N NaOH, MeOH; (b) EDC, HOBt, DCM / DMF, HNR 5 V.
  • Scheme VI above shows a general method for preparing compounds of formula 19 of this invention when Z, R, R 5 and V are as described herein. Each of the above steps is well known to one of skill in the art.
  • the present invention provides compounds that are inhibitors of protein kinases, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease.
  • pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al ., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 .
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980 ) discloses various carriers used in formulating pharmaceutically acceptable composition
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
  • a method for the treatment or lessening the severity of a Tec family comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof.
  • an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease, an Aurora family-mediated disease or a c-Met-mediated disease.
  • the compounds and compositions, according the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease, an Aurora family-mediated disease or a c-Met-mediated disease.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as, for example, water or other solvents, solubil
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention are useful as inhibitors of protein kinases.
  • the compounds and compositions of the invention are inhibitors of one or more of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or a c-Met family kinase, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation of one or more of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met is implicated in the disease, condition, or disorder.
  • a Tec family e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx
  • Tec family e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk
  • an Aurora family kinase or c-Met is implicated in a particular disease, condition, or disorder
  • the disease, condition, or disorder may also be referred to as a "Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease", "an Aurora family-mediated disease” or "a c-Met-mediated disease” or disease symptom.
  • the compounds of the present invention may be used in a method for treating or lessening the severity of a disease, condition, or disorder where activation or one or more of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met is implicated in the disease state.
  • Tec family e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk
  • the activity of a compound utilized in this invention as an inhibitor of a Tec family may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met.
  • Alternate in vitro assays quantitate the ability of the inhibitor to bind to a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met.
  • Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound.
  • inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met bound to known radioligands.
  • Tec family e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk
  • kinase activity means a measurable change in kinase activity between a sample comprising a compound of the invention and a kinase of interest and an equivalent sample comprising the kinase in the absence of said compound.
  • Tec family tyrosine kinases-mediated condition means any disease or other deleterious condition in which Tec family kinases are known to play a role.
  • Such conditions include, without limitation, autoimmune, inflammatory, proliferative, and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • AIDS Acquired Immunodeficiency Syndrome
  • Tec family tyrosine kinases -mediated conditions include diseases of the respiratory tract including, without limitation, reversible obstructive airways diseases including asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma airways hyper-responsiveness) and bronchitis.
  • Tec family tyrosine kinases diseases include, without limitation, those conditions characterised by inflammation of the nasal mucus membrane, including acute rhinitis, allergic, atrophic thinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis, sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia.
  • Tec family tyrosine kinases -mediated conditions also include diseases of the bone and joints including, without limitation, (pannus formation in) rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, and systemic sclerosis.
  • Tec family kinases-mediated conditions also include diseases and disorders of the skin, including, without limitation, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata and vernal conjunctivitis.
  • Tec family tyrosine kinases-mediated conditions also include diseases and disorders of the gastrointestinal tract, including, without limitation, Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g. migraine, rhinitis and eczema.
  • Tec family tyrosine kinases-mediated conditions also include those diseases and disorders of other tissues and systemic disease, including, without limitation, multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following angioplasty, tumours (for example leukemia, lymphomas), artherosclerosis, and systemic lupus erythematosus.
  • AIDS acquired immunodeficiency syndrome
  • lupus erythematosus systemic lupus
  • erythematosus Hashimoto's thyroiditis
  • Tec family tyrosine kinases-mediated conditions also include allograft rejection including, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
  • the invention provides the use of one of the above-described pharmaceutical compositions in the manufacture of a medicament for treating or preventing an Aurora-mediated condition.
  • that method is used to treat or prevent a condition selected from cancers such as cancers of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung, including lung adenocarcinoma and small cell lung cancer; stroke, diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease or disorder described above.
  • cancers such as cancers of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung, including lung adenocarcinoma and small cell lung cancer; stroke, diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease or disorder described above.
  • the invention relates to a method of inhibiting c-Met kinase activity in a biological sample in vitro comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • c-Met-mediated disease or "c-Met-mediated condition” means any disease state or other deleterious condition in which c-Met is known to play a role.
  • c-Met-mediated disease or "c-Met-mediated condition” also mean those diseases or conditions that are alleviated by treatment with a c-Met inhibitor.
  • Such conditions include, without limitation, renal, gastric, colon, brain, breast, prostate, and lung cancer, glioblastoma, atherosclerosis, lung fibrosis, conditions associated with organ transplantation, allergic disorders, and autoimmune disorders.
  • c-Met is synonymous with “cMet”, “MET”, “Met” or other designations known to one skilled in the art.
  • the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for treating or lessening the severity of renal, gastric, colon, brain, breast, prostate, and lung cancer, glioblastoma, atherosclerosis, lung fibrosis, conditions associated with organ transplantation, allergic disorders, or autoimmune disorders in a patient in need thereof.
  • the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for treating or lessening the severity of gastric or brain cancer in a patient in need thereof.
  • the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for treating or lessening the severity of renal cancer in a patient in need thereof.
  • the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for treating or lessening the severity of gastric cancer in a patient in need thereof.
  • Another aspect of the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for inhibiting tumor metastasis in a patient in need thereof.
  • biological sample means a sample outside a living organism, and includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of protein kinase, e.g., inhibition of c-Met, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • Another embodiment of the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for inhibiting protein kinase activity in a patient.
  • Said protein kinases include, but are not limited to, the protein kinases listed above.
  • the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated".
  • chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer.
  • known chemotherapeutic agents include, but are not limited to,
  • other therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention include surgery, radiotherapy (in but a few examples, gamma.-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, If
  • agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept ® and Excelon ® ; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex ® and Rebif ® ), Copaxone ® , and mitoxantrone; treatments for asthma such as albuterol and Singular ® ; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosup
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • Vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation.
  • a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562 ; 5,886,026 ; and 5,304,121 .
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Rt(min) refers to the HPLC retention time, in minutes, associated with the compound. Unless otherwise indicated, the HPLC method utilized to obtain the reported retention time is as follows:
  • 6-Bromo-3-pyridin-2-yl-pyrazolo[1,5- a ]pyrimidin-2-ylamine 50mg, 0.17mmol
  • 4-hydroxyphenylboronic acid 48 mg, 0.35 mmol
  • Aqueous 2M Na 2 CO 3 0.69 mmol
  • [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex in dichloromethane (1:1 ratio, 8mg, 0.010mmol was added and the mixture was heated in a microwave at 120°C for 20 minutes.
  • Example 7 A variety of other compounds have been prepared by methods substantially similar to those described herein Example 7. The characterization data for some of these compounds are summarized in Table 6 below and include HPLC, LC/MS (observed) and 1 H NMR data.
  • Reagents and conditions (a) DMF-DMA, 85°C, 16 hours; (b) EtOH, AcOH, microwave irradiation, 120°C, 30 minutes.
  • Scheme VII above shows another general synthetic route that has been used for preparing compounds D of this invention when Z, R, R 3 and R 4 are as described herein.
  • Intermediate B is prepared according to Scheme VII step (a) from Compound A .
  • Pyrazolo[1,5-a]pyrimidines ( D ) are prepared by microwave assisted cyclization of diamino-pyrazoles C with enaminones B .
  • 6-methyl-3-(6-(methylsulfinyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine 60 mg, 0.21 mmol was dissolved in NMP with nipecotamide (100 mg, 0.78 mmol)and heated to 200 °C in a microwave for 20 min.
  • the reaction mixture was purified by RP HPLC (C18, CH3CN/H2O 0.1 % TFA) and the pure fractions were poured into ethyl acetate/ 0.5 N NaOH.
  • Compounds are screened for their ability to inhibit Itk using a radioactive-phosphate incorporation assay. Assays are carried out in a mixture of 100 mM HEPES (pH 7.5), 10mM MgCl2, 25mM NaCl, 0.01 % BSA and 1mM DTT. Final substrate concentrations are 15 ⁇ M [ ⁇ -33P]ATP (400mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 2 ⁇ M peptide (SAM68 protein D332-443). Assays are carried out at 25 °C. in the presence of 30 nM Itk.
  • An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 50 ⁇ L of the stock solution is placed in a 96 well plate followed by addition of 1.5 ⁇ L of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15 ⁇ M with 2-fold serial dilutions) in duplicate (final DMSO concentration 1.5%). The plate is pre-incubated for 10 minutes at 25°C and the reaction initiated by addition of 50 ⁇ L [ ⁇ -33P]ATP (final concentration 15 ⁇ M).
  • the reaction is stopped after 10 minutes by the addition of 50 ⁇ L of a TCA / ATP mixture (20% TCA, 0.4mM ATP).
  • a Unifilter GF/C 96 well plate (Perkin Elmer Life Sciences, Cat no. 6005174) is pretreated with 50 ⁇ L Milli Q water prior to the addition of the entire reaction mixture (150 ⁇ L). The plate is washed with 200 ⁇ L Milli Q water followed by 200mL of a TCA / ATP mixture (5% TCA, 1mM ATP). This wash cycle is repeated a further 2 times. After drying, 30 ⁇ L Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) is added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
  • IC 50 data are calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1mM DTT. Final substrate concentrations in the assay are 7.5 ⁇ M [ ⁇ -33P]ATP (400mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 3 ⁇ M peptide (SAM68 protein D332-443). Assays are carried out at 25°C in the presence of 50 nM Itk. An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest.
  • 50 ⁇ L of the stock solution is placed in a 96 well plate followed by addition of 2 ⁇ L of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 50 ⁇ M with 2-fold serial dilutions) in duplicate (final DMSO concentration 2%).
  • the plate is pre-incubated for 10 minutes at 25°C and the reaction initiated by addition of 50 ⁇ L [ ⁇ -33P]ATP (final concentration 7.5 ⁇ M).
  • the reaction is stopped after 10 minutes by the addition of 100mL 0.2M phosphoric acid + 0.01% TWEEN 20.
  • a multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHNOB50) is pretreated with 100 ⁇ L 0.2M phosphoric acid + 0.01% TWEEN 20 prior to the addition of 170mL of the stopped assay mixture.
  • the plate is washed with 4 x 200 ⁇ L 0.2M phosphoric acid + 0.01% TWEEN 20.
  • 30 ⁇ L Optiphase 'SuperMix' liquid scintillation cocktail Perkin Elmer is added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
  • Ki(app) data are calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA,1mM DTT, 2.5 mM phosphoenolpyruvate, 300 ⁇ M NADH, 30 ⁇ g/ml pyruvate kinase and 10 ⁇ g/ml lactate dehydrogenase.
  • Final substrate concentrations in the assay are 100 ⁇ M ATP (Sigma Chemicals) and 3 ⁇ M peptide (Biotinylated SAM68 D332-443). Assays are carried out at 25°C and in the presence of 100nM Itk.
  • An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 60 ⁇ l of the stock solution is placed in a 96 well plate followed by addition of 2 ⁇ l of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15 ⁇ M). The plate is preincubated for 10 minutes at 25°C and the reaction initiated by addition of 5 ⁇ l of ATP. Initial reaction rates are determined with a Molecular Devices SpectraMax Plus plate reader over a 10 minute time course. IC50 and Ki data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • compounds of the invention including compounds in Table 1, are effective for the inhibition of ITK.
  • Compounds are screened for their ability to inhibit Btk using a radioactive-phosphate incorporation assay at Vertex Pharmaceuticals. Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1mM DTT. Final substrate concentrations in the assay are 50 ⁇ M [ ⁇ -33P]ATP (200mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech, Amersham, UK / Sigma Chemicals) and 2 ⁇ M peptide (SAM68 D332-443). Assays are carried out at 25°C and in the presence of 25 nM Btk.
  • An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of the peptide and the test compound of interest.
  • 75 ⁇ L of the stock solution is placed in a 96 well plate followed by addition of 2 ⁇ L of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15 ⁇ M) in duplicate (final DMSO concentration 2%).
  • the plate is preincubated for 15 minutes at 25°C and the reaction initiated by addition of 25 ⁇ L peptide (final concentration 2 ⁇ M). Background counts are determined by the addition of 100mL 0.2M phosphoric acid + 0.01% TWEEN to control wells containing assay stock buffer and DMSO prior to initiation with peptide.
  • the reaction is stopped after 10 minutes by the addition of 100mL 0.2M phosphoric acid + 0.01% TWEEN.
  • a multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) is pretreated with 100 ⁇ L 0.2M phosphoric acid + 0.01% TWEEN 20 prior to the addition of 170mL of the stopped assay mixture.
  • the plate is washed with 4 x 200 ⁇ L 0.2M phosphoric acid + 0.01% TWEEN 20.
  • 30 ⁇ L Optiphase 'SuperMix' liquid scintillation cocktail Perkin Elmer is added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
  • Ki(app) data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • Compounds are screened for their ability to inhibit Btk using an AlphaScreenTM phosphotyrosine assay at Vertex Pharmaceuticals. Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1mM DTT. Final substrate concentrations in the assay are 50 ⁇ M ATP (Sigma Chemicals) and 2 ⁇ M peptide (Biotinylated SAM68 D332-443). Assays are carried out at 25 °C and in the presence of 25 nM Btk. An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of peptide and the test compound of interest.
  • 37.5 ⁇ L of the stock solution is placed in each well of a 96 well plate followed by 1 ⁇ L of DMSO containing serial dilutions of the test compound (typically starting from a final concentration of 15 ⁇ M) in duplicate (final DMSO concentration 2%).
  • the plate is preincubated for 15 minutes at 25°C and the reaction initiated by addition of 12.5 ⁇ L peptide (final concentration 2 ⁇ M). Background counts are determined by the addition of 5 ⁇ L 500mM EDTA to control wells containing assay stock buffer and DMSO prior to initiation with Biotin-SAM68.
  • the reaction is stopped after 30 minutes by diluting the reaction 225-fold into MOPS buffer (20mM MOPS (pH 7.0), 1mM DTT, 10mM MgCl2, 0.1% BSA) containing 50mM EDTA to bring the final concentration of peptide to 9nM.
  • MOPS buffer 20mM MOPS (pH 7.0), 1mM DTT, 10mM MgCl2, 0.1% BSA) containing 50mM EDTA to bring the final concentration of peptide to 9nM.
  • AlphaScreenTM reagents are prepared according to the manufacturers instructions (AlphaScreenTM phosphotyrosine (P-Tyr-100) assay kit, PerkinElmer catalogue number 6760620C). Under subdued lighting, 20 ⁇ L of AlphaScreenTM reagents are placed in each well of a white half area 96 well plate (Corning Inc. - COSTAR 3693) with 30 ⁇ L of the stopped, diluted kinase reactions. Plates are incubated in the dark for 60 minutes prior to reading on a Fusion Alpha plate reader (PerkinElmer).
  • Ki(app) data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • compounds of the invention including compounds in Table 1, are effective for the inhibition of Btk.
  • Compounds are screened for their ability to inhibit Rlk using a standard coupled enzyme assay ( Fox et al., Protein Sci., (1998) 7, 2249 ). Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1mM DTT. Final substrate concentrations in the assay are 100 ⁇ M ATP (Sigma Chemicals) and 10 ⁇ M peptide (Poly Glu:Tyr 4:1). Assays are carried out at 30 °C and in the presence of 40nM Rlk.
  • Final concentrations of the components of the coupled enzyme system are 2.5 mM phosphoenolpyruvate, 300 ⁇ M NADH, 30 ⁇ g/ml pyruvate kinase and 10 ⁇ g/ml lactate dehydrogenase.
  • An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 60 ⁇ l of the stock solution is placed in a 96 well plate followed by addition of 2 ⁇ l of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 7.5 ⁇ M). The plate is preincubated for 10 minutes at 30°C and the reaction initiated by addition of 5 ⁇ l of ATP. Initial reaction rates are determined with a Molecular Devices SpectraMax Plus plate reader over a 10 minute time course. IC50 and Ki data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • compounds of the invention including compounds in Table 1, are effective for the inhibition of RLK.
  • the plates are then washed with PBST, 100 ⁇ L HRP-Conjugated 4010 antibody is added, and the plate incubated for 90 minutes at 30°C.
  • the plate is again washed with PBST, 100 ⁇ L TMB solution is added, and the plates are incubated for another 30 minutes at 30°C.
  • Sulfuric acid 100 ⁇ L of 1M is added to stop the reaction and the plate is read at 450 nm to obtain the optical densities for analysis to determine K i values.
  • Compound inhibition of JAK may also be assayed in the following manner: Compounds are screened for their ability to inhibit JAK3 using the assay shown below. Reactions are carried out in a kinase buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM MgCl 2 , 25 mM NaCl, and 0.01% BSA. Substrate concentrations in the assay are 5 ⁇ M ATP (200 uCi/ ⁇ mole ATP) and 1 ⁇ M poly(Glu) 4 Tyr. Reactions are carried out at 25 °C and 1 nM JAK3.
  • each well of a 96 well polycarbonate plate is added 1.5 ⁇ l of a candidate JAK3 inhibitor along with 50 ⁇ l of kinase buffer containing 2 ⁇ M poly(Glu) 4 Tyr and 10 ⁇ M ATP. This is then mixed and 50 ⁇ l of kinase buffer containing 2 nM JAK3 enzyme is added to start the reaction. After 20 minutes at room temperature (25C), the reaction is stopped with 50 ⁇ l of 20% trichloroacetic acid (TCA) that also contained 0.4 mM ATP. The entire contents of each well are then transferred to a 96 well glass fiber filter plate using a TomTek Cell Harvester. After washing, 60 ⁇ l of scintillation fluid is added and 33 P incorporation detected on a Perkin Elmer TopCount.
  • TCA trichloroacetic acid
  • compounds of the invention are effective for the inhibition of JAK (e.g., JAK-3).
  • An assay buffer solution is prepared which consists of 25 mM HEPES (pH 7.5), 10 mM MgCl 2 , 0.1% BSA and 10% glycerol.
  • a 22 nM Aurora-B solution also containing 1.7 mM DTT and 1.5 mM Kemptide (LRRASLG), is prepared in assay buffer.
  • the enzyme reaction is initiated by the addition of 16 ⁇ l stock [ ⁇ - 33 P]-ATP solution (-20 nCi/ ⁇ L) prepared in assay buffer, to a final assay concentration of 800 ⁇ M.
  • the reaction is stopped after 3 hours by the addition of 16 ⁇ L 500 mM phosphoric acid and the levels of 33 P incorporation into the peptide substrate is determined by the following method.
  • a phosphocellulose 96-well plate (Millipore, Cat no. MAPHNOB50) is pretreated with 100 ⁇ L of a 100 mM phosphoric acid prior to the addition of the enzyme reaction mixture (40 ⁇ L). The solution is left to soak on to the phosphocellulose membrane for 30 minutes and the plate subsequently is washed four times with 200 ⁇ L of a 100 mM phosphoric acid. To each well of the dry plate is added 30 ⁇ L of Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
  • Levels of non-enzyme catalysed background radioactivity are determined by adding 16 ⁇ L of the 500 mM phosphoric acid to control wells, containing all assay components (which acts to denature the enzyme), prior to the addition of the [ ⁇ - 33 P]-ATP solution.
  • Levels of enzyme catalysed 33 P incorporation are calculated by subtracting mean background counts from those measured at each inhibitor concentration. For each Ki determination 8 data points, typically covering the concentration range 0 -10 ⁇ M compound, are obtained in duplicate (DMSO stocks are prepared from an initial compound stock of 10 mM with subsequent 1:2.5 serial dilutions). Ki values are calculated from initial rate data by non-linear regression using the Prism software package (Prism 3.0, Graphpad Software, San Diego, CA).
  • Compounds are screened for their ability to inhibit Aurora-2 using a standard coupled enzyme assay ( Fox et al., Protein Sci., (1998) 7, 2249 ). Assays are carried out in a mixture of 100mM Hepes (pH7.5), 10mM MgCl 2 , 1mM DTT, 25mM NaCl, 2.5mM phosphoenolpyruvate, 300 ⁇ M NADH, 30 ⁇ g/ml pyruvate kinase and 10 ⁇ g/ml lactate dehydrogenase. Final substrate concentrations in the assay are 400 ⁇ M ATP (Sigma Chemicals) and 570 ⁇ M peptide (Kemptide, American Peptide, Sunnyvale, CA). Assays are carried out at 30 °C and in the presence of 40nM Aurora-2.
  • An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of Aurora-2 and the test compound of interest. 55 ⁇ l of the stock solution is placed in a 96 well plate followed by addition of 2 ⁇ l of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 7.5 ⁇ M). The plate is preincubated for 10 minutes at 30°C and the reaction initiated by addition of 10 ⁇ l of Aurora-2. Initial reaction rates are determined with a Molecular Devices SpectraMax Plus plate reader over a 10 minute time course. IC50 and Ki data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • Final concentrations of the components of the coupled enzyme system are 2.5 mM phosphoenolpyruvate, 300 ⁇ M NADH, 30 ⁇ g/ml pyruvate kinase and 10 ⁇ g/ml lactate dehydrogenase.
  • An assay stock buffer solution is prepared containing all of the reagents listed above with the exception of ATP and a test compound of the present invention.
  • the assay stock buffer solution (175 ⁇ l) is incubated in a 96 well plate with 5 ⁇ l of the test compound of the present invention at final concentrations spanning 0.006 ⁇ M to 12.5 ⁇ M at 30 °C for 10 minutes.
  • a 12-point titration is conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds of the present invention in daughter plates.
  • the reaction is initiated by the addition of 20 ⁇ l of ATP (final concentration 200 ⁇ M). Rates of reaction are obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 minutes at 30 °C.
  • the K i values are determined from the rate data as a function of inhibitor concentration.
  • Table 11 depicts enzyme inhibition data (K i ) for certain exemplary compounds.
  • Compound numbers in Table 11 corresponds to those compounds depicted in Table 5.
  • “A” represents a K i of less than 0.5 ⁇ M
  • “B” represents a K i of between 0.5 and less than 5.0 ⁇ M
  • “C” represents a K i of greater than or equal to 5.0 ⁇ M for the indicated enzyme.
  • Table 11 Biological Characterization Data for Selected Compounds Cmpd # (V-) AurA AurB ITK JAK3 Met RLK 1 C 2 B C B 3 B C B 4 B C B 5 B C B 6 B B B 7 B C B 8 B C B 9 B C B 10 B C B 11 B C B 12 B C B 13 B C B 14 B B C B 15 B C B 16 B C B 17 B C B 18 A A C A 19 B C B 20 B C B 21 B C B 22 B B C A 23 B C B 24 B B C B 25 B C B 26 B C B 27 B C B 28 B C B 29 B C B 30 B C B 31 B C B 32 B C B 33 B B C B 34 B C B 35 B C B 36 B C B 37 B C B 38 B C B 39 B C B 40 B C B 41 B C B 42 B C B 43 B C B 44 B C B 45 B C B 46 B C B 47 B C B 48 B C B 49 B C B 50 B C A 51 B A B A 52 B C B 53 B C A 54 B

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Abstract

The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing the compounds of the invention.

Description

    TECHNICAL FIELD OF THE INVENTION
  • The present invention relates to compounds useful as inhibitors of protein kinases, particularly Tec family kinases, Aurora kinases and c-Met. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and the use of the compositions in the manufacture of medicaments for the treatment of various disorders. The invention also provides processes for preparing the compounds of the invention.
    • BACKGROUND OF THE INVENTION
  • The Tec family of non-receptor tyrosine kinases plays a central role in signalling through antigen-receptors such as the TCR, BCR and Fcε receptors and are essential for T cell activation. Deletion of Itk in mice results in reduced T cell receptor (TCR)-induced proliferation and secretion of the cytokines IL-2, IL-4, IL-5, IL-10 and IFN-γ. Itk has been implicated in allergic asthma and atopic dermatitis.
  • Tec family kinases are also essential for B cell development and activation. Patients with mutations in Btk have a profound block in B cell development, resulting in the almost complete absence of B lymphocytes and plasma cells, severely reduced Ig levels and a profound inhibition of humoral response to recall antigens. Btk deletion in mice has a profound effect on B cell proliferation induced by anti-IgM, and inhibits immune responses to thymus-independent type II antigens.
  • Tec kinases also play a role in mast cell activation through the high-affinity IgE receptor (FcεRI). Itk and Btk are expressed in mast cells and are activated by FcεRI cross-linking. Btk deficient murine mast cells have reduced degranulation and decreased production of proinflammatory cytokines following FcεRI cross-linlting. Btk deficiency also results in a decrease of macrophage effector functions.
  • The Aurora proteins are a family of three highly related serine/threonine kinases (termed Aurora-A, -B and -C) that are essential for a cell's progression through the mitotic phase of the cell cycle. Specifically Aurora-A plays a crucial role in centrosome maturation and segregation, formation of the mitotic spindle, and faithful segregation of chromosomes. Aurora-B is a chromosomal passenger protein that plays a central role in regulating the alignment of chromosomes on the meta-phase plate, in the spindle assembly checkpoint, and also in the correct completion of cytokinesis.
  • Overexpression of Aurora-A (Aurora-2), Aurora-B (Aurora-1) or Aurora-C has been observed in a range of human cancers including colorectal, ovarian, gastric, and invasive duct adenocarcinomas.
  • A number of studies have now demonstrated that depletion or inhibition of Aurora-A or -B in human cancer cell lines by siRNA, dominant negative or neutralizing antibodies, disrupts progression through mitosis with accumulation of cells with 4N DNA. In some cases, this is followed by endoreduplication and cell death.
  • The c-Met receptor tyrosine kinase is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. The various cancers in which c-Met is implicated include, but are not limited to, gastric adenocarcinoma, renal cancer, small cell lung carcinoma, colorectal cancer, colon cancer, prostate cancer, brain cancer, liver cancer, pancreatic cancer, and breast cancer. c-Met is also implicated in atherosclerosis, lung fibrosis, allergic disorders, autoimmune disorders, and conditions associated with organ transplantation.
  • Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. In particular, it would be desirable to develop compounds that are useful as inhibitors of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) and Aurora family protein kinases, as well as c-Met, particularly given the inadequate treatments currently available for the majority of the disorders implicated in their activation.
  • WO 98/54093 , WO 2004/052315 A2 and WO 00/53605 describe compounds useful to treat tyrosine kinase-dependent diseases and conditions. WO 02/066481 A1 describe pyrimidine derivatives for inhibition of cell proliferation.
    • SUMMARY OF THE INVENTION
  • It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of protein kinases. In certain embodiments, these compounds are effective as inhibitors Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases, Aurora family kinases and/or c-Met. These compounds have the formulae I', II, III or IV as defined herein, or a pharmaceutically acceptable salt thereof.
  • These compounds and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions. The compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention relates to a compound of formula I':
    Figure imgb0001
     or a pharmaceutically accepted salt thereof, wherein
    R is -(C=Q)R2a, CN, or Y; wherein
    • Y
    is a 5-10 membered monocyclic or bicyclic heterocyclyl, aryl, or heteroaryl ring; each Y is independently and optionally substituted with 0-5 JY;
    Q
    is O, NH, NR', or S;
    R'
    is C1-6alkyl optionally substituted with 0-4 occurrences of halo, C1-6aliphatic, NO2, NH2, -N(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1-6alkyl), OH, -O(C1-6alkyl), -C(O)(C1-6alkyl), -C(O)NH2, -C(O)N(C1-6alkyl), or -C(O)N(C1-6alkyl)2;
    R2a
    is C1-6aliphatic, C6-10aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, OR5, or N(R5)2; each R2a is independently and optionally substituted with 0-5 J2a;
    R1
    is H, -C(O)(C1-6alkyl), -C(O)O(C1-6alkyl), -C(O)NH2, -C(O)N(C1-6alkyl), -C(O)N(C1- 6alkyl)2; or C1-6 aliphatic; each R1 is optionally substituted with 0-4 occurrences of halo, C1-6haloalkyl, C1-6aliphatic, NO2, NH2, -N(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1- 6alkyl), OH, or -O(C1-6alkyl);
    Z
    is a bond or C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement;
    R3
    and R4 are each independently H, halogen, C1-6alkoxy, N(R5)2, CN, NO2, or Um-V wherein m is 0 or 1;
    V
    is H, C6-10 aryl, 5-10 membered heteroaryl. C3-10 cycloaliphatic, 5-10 membered heterocyclyl, or C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement; V is optionally substituted with 0-4 R8;
    U
    is C1-12 alkylidene chain wherein up to two methylene units of the chain are optionally and independently replaced by -NH-, -NR2- -O-, -S-, -CO2-, -OC(O)-, -C(O)CO-, -C(O)- -C(O)NH-, -C(O)NR5-, -C(=N-CN), -NHCO-, -NR5CO-, -NHC(O)O-, -NR5C(O)O-, SO2NH-, -SO2NR5-, -NHSO2-, -NR5SO2-, -NHC(O)NH-, -NR5C(O)NH-, -NHC(O)NR5-, -NR5C(O)NR5, -OC(O)NH-, -OC(O)NR5-, -NHNH-, -NHNR5-, -NR5NR5-, -NR5NH-, -NHSO2NH-, -NR5SO2NH-, -NHSO2NR5-, -NR5SO2NR5-, -SO-, -SO2-, -PO-, -PO2- or -POR5-; U is optionally substituted with 0-6 JU;
    R5
    is C1-4haloalkyl, -C(O)COR6, -C(O)R6, -C(O)OR6, -C(O)N(R6)2, -SO2R6, C0-6alkyl-heterocyclyl, C0-6alkyl-heteroaryl, C0-6alkyl-aryl, C0-6alkyl-cycloaliphatic or C1-6 aliphatic wherein up to three methylene unit of the aliphatic chain are optionally and independently replaced by -NR"-, -O-, -S-, -CO2-, -OC(O)-, -C(O)CO-, -C(O)-, -C(O)NR"- -NR"CO-, -NR"C(O)O-, -SO2NR"-, -NR"SO2-, -C(O)NR"NR"-, -NR"C(O)NR"- -OC(O)NR"- -NR"NR"-, -NR"SO2NR"-, -SO-, -SO2- -PO-, -PO2-, or -POR"- in a chemically stable arrangement; each R5 is independently and optionally substituted with 0-5 JR5; or two R5 groups taken together with the atom to which they are attached optionally join to form a 5-10 membered carbocyclic or heterocyclic ring; wherein said ring is optionally substituted with 0-4 J';
    R6
    is H, C1-6alkoxy, C1-4haloalkyl, C0-6alkyl-heterocyclyl, C0-6alkyl-heteroaryl, C0-6alkyl-aryl, C0-6alkyl-cycloaliphatic, or C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement; each R6 is independently and optionally substituted with 0-5 JR6; or two R6 groups taken together with the atom to which they are attached optionally join to form a 5-10 membered carbocyclic or heterocyclic ring; wherein said ring is optionally substituted with 0-4 J";
    R8
    is halogen, C1-4haloalkyl, phenyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, - OR6, -N(R6)2, -SR6, NO2, CN, -COOR6, -C(O)N(R6)2,_-SO2R6, -SO2N(R6)2, -NR6C(O)R6, -C(O)R6, -OC(O)R6, NR6C(O)O-R6, -NR6SO2-R6, -C(O)NR6N(R6)2, -NR6C(O)N(R6)2, -OC(O)N(R6)2, -NR6N(R6)2, -NR6SO2N(R6)2 or C1-12 aliphatic, wherein up to three methylene units of the aliphatic chain can be optionally interrupted with -C(O)R6, -C(O)O-, -OC(O)-, -C(O)-, -C(O)N(R6)-, -NR6CO(R6)-, -O-, -NR6- or -S-; each R8 is independently and optionally substituted with 0-5 JR8;
    each
    JY, J2a, Ju, JR5, JR6, JR8, J', and J" is independently selected from N(R9)2, SR9, OR9, halo, CN, N02, COOR9, C(O)R9, SO2R9, SOR9, -X-CF3, -X-SH, -X-OH, C1-4haloalkyl, C6- 10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3- 10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X;
    X
    is C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NH-, -NR"-, -O-, -S-, -CO2-, -OC(O)-, -C(O)CO-, -C(O)-, -C(O)NH-, -C(O)NR"-, -C(=N-CN), -NHCO-, -NR"CO- -NHC(O)O-, -NR"C(O)O-, -SO2NH-, -SO2NR"- -NHSO2-, -NR"SO2-, NHC(O)NH-, -NR"C(O)NH-, -NHC(O)NR"-, -NR"C(O)NR", -OC(O)NH-, -OC(O)NR"-, -NHNH-, -NHNR"- -NR"NR"-, -NR"NH-, -NHSO2NH-, -NR"SO2NH-, -NHSO2NR"-, -NR"SO2NR"-, -SO-, -SO2-, -PO-, -PO2-, or -POR"-; in a chemically stable arrangement; wherein R" is H or C1-6 aliphatic;
    each
    JY, J2a, Ju, JR5, JR6, J', and J" is optionally and independently substituted with 0-4 occurrences of N(R9)2, SR9, OR9, halo, CN, NO2, COOR9, C(O)R9, SO2R9, SOR9, -X- CF3, -X-SH, -X-OH, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X;
    R9
    is H, C1-6 aliphatic, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl) or X, or wherein two R9, taken together with the atom to which they are attached, form a 5-10 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 0-4 occurrences of halo, CN, NO2, -COOH, -COO(C1-6alkyl), -C(O)H, SO2H, SO2(C1-6alkyl), C1-6haloaliphatic, NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1-6alkyl), OH, -O(C1-6alkyl), -C(O)(C1-6alkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), -C(O)N(C1-6alkyl)2, -C(O)NH2, -C(O)NH(C1-6alkyl), or -C(O)N(C1-6alkyl)2, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X, whereby the following compounds are excluded: - 3-(2-amino-5-methyl-pyrazolo[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3- b]pyridine, - 5-phenyl-3-phenylazo-pyrazolo[1,5-a]pyrimidin-2-ylamine.
  • In some embodiments, the invention provides a compound selected from one of the following:
    Figure imgb0002
    Figure imgb0003
    Figure imgb0004
    Figure imgb0005
    Figure imgb0006
    Figure imgb0007
    Figure imgb0008
    Figure imgb0009
    Figure imgb0010
    Figure imgb0011
  • In some embodiments, the invention provides a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. In further embodiments, the composition further comprises an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • The invention also provides methods of inhibiting Tec family kinase activity in a biological sample in vitro comprising contacting said biological sample with, a compound of the invention or a composition comprising said compound. In futher embodiments, the method comprises inhibiting Itk activity. The invention also provides the use of a compound of the present invention or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of a disease of condition selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease. In further embodiments, the treatment comprises administering to said patient an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS), wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
  • In further embodiments, the disease or disorder is asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata vernal conjunctivitis, Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies, multiple sclerosis, artherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following angioplasty, tumours, artherosclerosis, systemic lupus erythematosus, allograft rejection including, without limitation, acute and chronic allograft rejection following for example , transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
  • The invention provides a compound of formula I':
    Figure imgb0012
     or a pharmaceutically accepted salt thereof, wherein R is -(C=Q)R2a, CN, or Y; wherein
    • Y
    is a 5-10 membered monocyclic or bicyclic heterocyclyl, aryl, or heteroaryl ring; each Y is independently and optionally substituted with 0-5 JY;
    Q
    is O, NH, NR', or S;
    R'
    is C1-6alkyl optionally substituted with 0-4 occurrences of halo, C1-6aliphatic, NO2, NH2, -N(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1-6alkyl), OH, -O(C1-6alkyl), -C(O)(C1-6alkyl), -C(O)NH2, -C(O)N(C1-6alkyl), or -C(O)N(C1-6alkyl)2;
    R2a
    is C1-6aliphatic, C6-10aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, OR5, or N(R5)2; each R2a is independently and optionally substituted with 0-5 J2a;
    R1
    is H, -C(O)(C1-6alkyl), -C(O)O(C1-6alkyl), -C(O)NH2, -C(O)N(C1-6alkyl), -C(O)N(C1- 6alkyl)2; or C1-6 aliphatic; each R1 is optionally substituted with 0-4 occurrences of halo, C1-6haloalkyl, C1-6aliphatic, NO2, NH2, -N(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1-6alkyl), OH, or -O(C1-6alkyl);
    Z
    is a bond or C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement;
    R3 and R4
    are each independently H, halogen, C1-6 alkoxy, N(R5)2, CN, NO2, or Um-V wherein m is 0 or 1;
    V
    is H, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloaliphatic, 5-10 membered heterocyclyl, or C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement; V is optionally substituted with 0-4 R8;
    U
    is C1-12 alkylidene chain wherein up to two methylene units of the chain are optionally and independently replaced by -NH-, -NR5-, -O-, -S-, -CO2-, -OC(O)-, -C(O)CO- , -C(O)-, -C(O)NH-, -C(O)NR5-, -C(=N-CN), -NHCO-, -NR5CO-, -NHC(O)O-, -NR5C(O)O-, -SO2NH-, -SO2NR5-, -NHSO2-, -NR5SO2-, -NHC(O)NH-, -NRC(O)N-H-, -NHC(O)NR5-, -NR5C(O)NR5, -OC(O)NH-, -OC(O)NR5-, -NHNH-, -NHNR5-, -NR5NR5 -, -NR5NH-, -NHSO2NH-, -NR5SO2NH-, -NHSO2NR5-, -NR5SO2NR5-, -SO-, -SO2-, -PO-, -PO2-, or -POR5-; U is optionally substituted with 0-6 JU;
    R5
    is C1-4haloalkyl, -C(O)COR6,-C(O)R6, -C(O)OR6, -C(O)N(R6)2, -SO2R6, C0-6alkyl-heterocyclyl, C0-6alkyl-heteroaryl, C0-6alkyl-aryl, C0-6alkyl- cycloaliphatic or C1-6 aliphatic wherein up to three methylene unit of the aliphatic chain are optionally and independently replaced by -NR"-, -O-, -S-, -CO2-, - OC(O)-, -C(O)CO-, -C(O)-, -C(O)NR"-, -NR"CO-, -NR"C(O)O-, -SO2NR"-, -NR"SO2-, -C(O)NR"NR"-, -NR"C(O)NR"-, -OC(O)NR"-, "NR"NR"-, -NR"SO2NR"-, -SO-, -SO2-, -PO-, -PO2-, or -POR"- in a chemically stable arrangement; each R5 is independently and optionally substituted with 0-5 JR5; or two R5 groups taken together with the atom to which they are attached optionally join to form a 5-10 membered carbocyclic or heterocyclic ring; wherein said ring is optionally substituted with 0-4 J' ;
    R6
    is H, C1-6alkoxy, C1-4haloalkyl, C0-6alkyl-heterocyclyl, C0-6alkyl-heteroaryl, C0-6alkyl- aryl, C0-6alkyl-cycloaliphatic, or C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement; each R6 is independently and optionally substituted with 0-5 JR6; or two R6 groups taken together with the atom to which they are attached optionally join to form a 5-10 membered carbocyclic or heterocyclic ring; wherein said ring is optionally substituted with 0-4 J";
    R8
    is halogen, C1-4haloalkyl, phenyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, -OR6, -N(R6)2, -SR6, NO2, CN, -COOR6, -C(O)N(R6)2, -SO2R6,- SO2N(R6)2, -NR6C(O)R6, -C(O)R6, -OC(O)R6, -NR6C(O)O-R6, -NR6SO2-R6, -C(O)NR6N(R6)2, -NR6C(O)N(R6)2, -OC(O)N(R6)2, -NR6N(R6)2, -NR6SO2N(R6)2 or C1-12 aliphatic, wherein up to three methylene units of the aliphatic chain can be optionally interrupted with -C(O)R6, -C(O)O-, -OC(O)-, -C(O)-, -C(O)N(R6)-, -NR6CO(R6)-, -O-, -NR6-, or -S-; each R8 is independently and optionally substituted with 0-5 JR8;
    each JY, J2a, Ju, JR5, JR6, JR8, J', and J"
    is independently selected from N(R9)2, SR9, OR9, halo, CN, NO2, COOR9, C(O)R9, SO2R9, SOR9, -X-CF3, -X-SH, -X-OH, C1- 4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X;
    X
    is C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NH-, -NR"-, -O-, -S-, -CO2-, -OC(O)-, -C(O)CO-, -C(O)-, -C(O)NH-, -C(O)NR"-, -C(=N-CN), -NHCO-, -NR"CO-, -NHC(O)O-, -NR"C(O)O-, -SO2NH-, -SO2NR"-, -NHSO2-, -NR"SO2-, -NHC(O)NH-, -NR"C(O)NH-, -NHC(O)NR"-, -NR"C(O)NR", -OC(O)NH-, -OC(O)NR"-, -NHNH-, -NHNR"-, -NR"NR"-, -NR"NH-, -NHSO2NH-, -NR"SO2NH-, -NHSO2NR"-, -NR"SO2NR"-, -SO-, -SO2-, -PO-, -PO2-, or -POR"-; in a chemically stable arrangement; wherein R" is H or C1-6 aliphatic;
    each JY, J2a, Ju, JR5, JR6, J', and J"
    is optionally and independently substituted with 0-4 occurrences of N(R9)2, SR9, OR9, halo, CN, NO2, COOR9, C(O)R9, SO2R9, SOR9, -X-CF3, -X-SH, -X-OH, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X;
    R9
    is H, C1-6 aliphatic, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl) or X, or wherein two R9, taken together with the atom to which they are attached, form a 5-10 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 0-4 occurrences of halo, CN, NO2, -COOH, -COO(C1-6alkyl), - C(O)H, SO2H, SO2(C1-6alkyl), C1-6haloaliphatic, NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1-6alkyl), OH, -O(C1-6alkyl), -C(O)(C1-6alkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), -C(O)N(C1-6alkyl)2, -C(O)NH2, -C(O)NH(C1-6alkyl), or -C(O)N(C1-6alkyl)2, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X
    whereby the following compounds are excluded:
    • 3-(2-amino-5-methyl-pyrazolo[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridine,
    • 5-phenyl-3-phenylazo-pyrazolo[1,5-a]pyrimidin-2-ylamine.
  • In some embodiments of formula I', if R4 is H, then R3 is other than H. In further embodiments, R4 is H and R3 is other than H. In other embodiments, Z is a bond. In other embodiments, R1 is H.
  • In some embodiments of formula I', R is
    Figure imgb0013
     In further embodiments, Q is N or O. In further embodiments, R2a is OR5, N(R5)2, or 5-8 membered heterocyclyl. In further embodiments, the 5-8 membered heterocyclyl contains 1-2 nitrogen atoms. In yet further embodiments, the 5-8 membered heterocyclyl is optionally substituted with 0-4 occurrences of C1-6aliphatic, C1-4haloalkyl, CN, halo, OH, O-(C1-6aliphatic), NH2, NH(C1-6aliphatic), N(C1-6aliphatic)2, benzyl, -CH2-(pyridyl), or -CH2-pyrrolidinyl.
  • In some embodiments of formula I', R2a is N(R5)2. In further embodiments, R5 is H or an optionally substituted group selected from 5-8 membered heterocyclyl, -(C1-6alkyl)-(5-8 membered heterocyclyl), 5-6 membered heteroaryl -(C1-6alkyl)-(5-6 membered heteroaryl), phenyl, -(C1-6alkyl)-(phenyl), C3-10cycloaliphatic, -(C1-6alkyl)-(C3-10cycloaliphatic) and C1-6 aliphatic wherein up to three methylene unit of the aliphatic chain are optionally and independently replaced by -NR"-, -O-, or -S- in a chemically stable arrangement. In yet further embodiments, R5 is H or an optionally substituted group selected from pyrrolidinyl, piperidinyl, piperazinyl, -CH2-(5-6 membered heteroaryl), phenyl, benzyl, and C1-6 aliphatic wherein up to one methylene unit of the aliphatic chain is optionally and independently replaced by -NR"-, -O-, or -Sin a chemically stable arrangement.
  • In some embodiments of formula I', JR5 is halo, CN, C1-4haloalkyl, or an optionally substituted group selected from phenyl, benzyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, CH2-(5-6 membered heteroaryl), CH2-(5-8 membered heterocyclyl), and C1-6aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NR"-, -O-, -S-, -C(O)-, -SO-, or -SO2-, in a chemically stable arrangement. In further embodiments, JR5 is halo, CN, phenyl, benzyl, CH2-(pyridyl), CH2-(pyrrolidinyl), or C1-6aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by - NR"-, -O-, or -S-.
  • In some embodiments of formula I', R is Y. In further embodiments, Y is an optionally substituted 5-10 membered heteroaryl or heterocyclyl. In yet further embodiments, Y is an optionally substituted 5-6 membered heteroaryl or 5-8 membered heterocyclyl. In yet further embodiments, Y is a pyridine ring optionally substituted with 0-4 JY. In further embodiments, Y is a 2-pyridine ring optionally substituted with 0-4 JY.
  • In some embodiments of formula I', JY is halo, CN, NO2, C1-6haloaliphatic, phenyl, benzyl, 5-6 membered heteroaryl, C1-6alkyl-(5-6 membered heteroaryl), C3-10 cycloaliphatic, (C1-6alkyl)-(C3-10 cycloaliphatic), 5-8 membered heterocyclyl, C1-6alkyl-(5-8 membered heterocyclyl), or C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NR-, -O-, -S-, -C(O)-, -SO-, or -SO2- in a chemically stable arrangement. In further embodiments, JY is halo, CN, NO2, CF3, C1-6 aliphatic, phenyl, benzyl, -O-benzyl, piperidinyl, pyrrolidinyl, -NR(C1-6alkyl), -O(C1-6alkyl), -S(C1-6alkyl), OH, SH, or NH2.
  • In some embodiments of formula I', R3 and R4 are each independently Um-V. In further embodiments, V is H, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloaliphatic, or 5-10 membered heterocyclyl optionally substituted with 0-4 R8. In further embodiments, V is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl, or 5-8 membered heterocyclyl. In yet further embodiments, V is an optionally substituted group selected from phenyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In still further embodiments, V is optionally substituted phenyl.
  • In some embodiments of formula I', R3 is Um-V; m is 1, and U is C1-6aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by -C(O)-, -C(O)NR5-, or -C(O)O-. In further embodiments, U is -C(O)NR5-. In yet further embodiments, V is optionally substituted phenyl or optionally substituted pyridyl.
  • In some embodiments of formula I', R3 is Um-V, m is zero and V is aryl or heteroaryl.
  • In some embodiments of formula I', R8 is halogen, C1-4haloalkyl, phenyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, -OR6, -N(R6)2, -SR6, NO2, CN, - COOR6, -C(O)N(R6)2, -SO2R6, -SO2N(R6)2, -NR6C(O)R6, -C(O)R6, -NR6SO2-R6, -C(O)NR6N(R6)2, or C1-12 aliphatic, wherein up to three methylene units of the aliphatic chain can be optionally interrupted with -C(O)R6, -C(O)O-, -OC(O)-, -C(O)-, -C(O)N(R6)-, -NR6CO(R6)-, -O-, -NR6-, or -S-. In further embodiments, R8 is -OR6, -N(R6)2, C(O)R6, -C(O)N(R6)2, or 5-7 membered heterocyclyl. In still further embodiments, R8 is -C(O)N(R6)2 or C(O)R6.
  • In certain embodiments of formula I', R6 is H or an optionally substituted group selected from 5-8 membered heterocyclyl, -(C1-6alkyl)-(5-8 membered heterocyclyl), benzyl, -(C1-6alkyl)-(5-8 membered heteroaryl), and C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement. In further embodiments, R6 is H or an optionally substituted group selected from a 5-8 membered heterocyclyl and C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement.
  • In some embodiments of formula I', JR6 is selected from C1-6alkyl, halo, CN, OH, -O(C1-6alkyl), NH2, -N(C1-6alkyl), and -N(C1-6alkyl)2. In some embodiments of formula I', J" is selected from C1-6aliphatic, halo, CN, OH, -O(C1-6alkyl), NH2, -N(C1-6alkyl), -N(C1-6alkyl)2, -C(O)OH, -C(O)O(C1-6alkyl), 5-6 membered heteroaryl, -CH2-(5-6 membered heteroaryl), 5-6 membered heterocyclyl, -CH2-(5-6 membered heterocyclyl), and C1-6aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement.
  • In some embodments of formula I', Z is a bond and R is selected from
    Figure imgb0014
    Figure imgb0015
  • In certain embodiments, R is selected from
    Figure imgb0016
    Figure imgb0017
  • In further embodiments, R is
    Figure imgb0018
  • In some embodiments of formula I', JY is selected from -X-(C6-10 aryl), -X-(5-10 membered heteroaryl), -X-(C3-10 cycloaliphatic), -X-(5-10 membered heterocyclyl), or X. In some embodiments, X is C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by NR"-, -O-, -S-, -C(O)-, -SO-, or -SO2-. In further embodiments, X is C1-12 aliphatic wherein up to one methylene unit is optionally and independently replaced by -NR"-. In yet further embodiments, at least one NR"- is directly attached to R.
  • In other embodiments of formula I', JY is an optionally substituted group selected from C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloaliphatic, and 5-10 membered heterocyclyl. In other embodiments, JY is halo, CN, NO2, CF3, OR", SR", or N(R")2.
  • In some embodiments of formula I', R is substituted with 2 occurrences of JY wherein one JY is selected from -X-(C6-10 aryl), -X-(5-10 membered heteroaryl), -X-(C3-10 cycloaliphatic), -X-(5-10 membered heterocyclyl), or X and the other JY is selected from H, halo, CN, NO2, CF3, OR", SR", N(R")2, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloaliphatic, or 5-10 membered heterocyclyl. In further embodiments, R is substituted with 2 occurrences of JY wherein one JY is selected from X and the other JY is selected from H, halo, CN, NO2, CF3, OR", SR", or N(R")2.
  • In some embodiments, the invention provides a compound of formula II:
    Figure imgb0019
     or a pharmaceutically accepted salt thereof, wherein Ring A is Y.
  • In further embodiments of formula II, if R4 is H, then R3 is other than H. In further embodiments, R4 is H and R3 is other than H.
  • In some embodiments, the invention provides a compound of formula III:
    Figure imgb0020
     or a pharmaceutically accepted salt thereof, wherein
    R3 is halogen, C1-6 aliphatic, C1-6 alkoxy, N(R5)2, CN, NO2, or Um-V;
    Ring A is a 5-8 membered monocyclic heteroaryl ring.
  • In some embodiments of formula III, Ring A has the formula
    Figure imgb0021
  • In further embodiments, Ring A has a formula selected from the group consisting of:
    Figure imgb0022
    Figure imgb0023
    Figure imgb0024
    Figure imgb0025
    Figure imgb0026
  • In some embodiments, the invention provides a compound of formula IV:
    Figure imgb0027
     wherein each of Z1 and Z2 is CH or N and R3 is as defined for formula III.
  • In some embodiments of formula IV, Z2 is CH. In some embodiments, Z1 is N or CH. In further embodiments, Z1 is N and Z2 is CH. In further embodiments, Z1 and Z2 are both CH.
  • In some embodiments of formula IV, R3 is C1-6 aliphatic. In further embodiments, R3 is C1-3 alkyl.
  • In some embodiments of formula IV, JY is optionally substituted -N(R9)2. In further embodiments, JY is optionally substituted -NHR9. In further embodiments, JY is optionally substituted-N(R9)2, wherein said two R9 form an optionally substituted 5-8 membered heterocyclyl.
  • In some embodiments, the invention provides a compound selected from Table 5.
  • In some embodiments, the invention provides a composition comprising a compound of formulae I' , II, III or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. In further embodiments, the composition comprises an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • In some embodiments, the invention provides a method of inhibiting Tec family kinase activity in a biological sample in vitro, which method comprises contacting said biological sample with, a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound. In further embodiments, the method comprises inhibiting Itk activity.
  • In some embodiments, the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of a disease of condition in a patient in need thereof, wherein said disease or condition is selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease. In further embodiments, the treatment comprises administering to said patient an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS), wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
  • In some embodiments, the disease or disorder to be treated is asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata vernal conjunctivitis, Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies, multiple sclerosis, artherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following angioplasty, tumours, artherosclerosis, systemic lupus erythematosus, allograft rejection including, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
  • In some embodiments, the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for inhibiting c-Met kinase activity in a patient or a biological sample.
  • In some embodiments, the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of a cancer in a patient in need thereof. In further embodiments, the treatment further comprises administering to said patient a chemotherapeutic-agent, wherein chemotherapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
  • In further embodiments, the cancer is renal cancer. In other embodiments, the cancer is selected from a glioblastoma, a gastric carcinoma or a cancer selected from colon, breast, prostate, brain, liver, pancreatic or lung cancer. In further embodiments, the cancer is gastric carcinoma. In other embodiments, the cancer is glioblastoma or a cancer selected from breast, colon or liver.
  • In other embodiments, the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for inhibiting or reducing the severity of tumor metastasis in a patient in need thereof.
  • In some embodiments, the invention provides a method of inhibiting Aurora kinase activity in a biological sample in vitro, which method comprises contacting said biological sample with, a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.
  • In some embodiments, the invention provides the use of a compound of formulae I', II, III or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof.
  • Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.
  • As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • The term "optionally interrupted" refers to the replacement of one atom within an alkylidene chain with another atom. Unless otherwise specified, the second atom can replace the first atom at any position, including terminal atoms. For example, a C1-3 alkyl chain optionally interrupted with -O- can form -OCH2CH3, -CH2-OCH3, or CH2CH2OH. Unless otherwise specified, the terminal groups are bonded to hydrogen on the terminal side.
  • The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • The term "heteroaliphatic", as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" groups.
  • The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
  • The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).
  • The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation.
  • The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom.
  • The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I.
  • The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring".
  • The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
  • An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halogen; -R°; -OR°; -SR°; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°; -(CH2)1-2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°; -NO2; -CN; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2; -NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2, - NR°NR°CO2R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -CO2R°; -C(O)R°; -C(S)R°; - C(O)N(R°)2; -C(S)N(R°)2; -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°)R°; -C(NOR°)R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; -NR°SO2N(R°)2; -NR°SO2R°; -N(OR°)R°; -C(=NH)-N(R°)2; or -(CH2)0-2NHC(O)R° wherein each independent occurrence of R° is selected from hydrogen, optionally substituted C1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or, notwithstanding the definition above, two independent occurrences of R°, on the same substituent or different substituents, taken together with the atom(s) to which each R° group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R° are selected from NH2, NH(C1-4aliphatic), N(C1-4aliphatic)2, halogen, C1-4aliphatic, OH, O(C1-4aliphatic), NO2, CN, CO2H, CO2(C1-4aliphatic), O(haloC1-4 aliphatic), or haloC1-4aliphatic, wherein each of the foregoing C1-4aliphatic groups of R° is unsubstituted.
  • An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where each R* is independently selected from hydrogen or an optionally substituted C1-6 aliphatic. Optional substituents on the aliphatic group of R* are selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, O(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O(halo C1-4 aliphatic), or halo(C1-4 aliphatic), wherein each of the foregoing C1-4aliphatic groups of R* is unsubstituted.
  • Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R+, -N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR+SO2R+; wherein R+ is hydrogen, an optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CH2(Ph), optionally substituted -(CH2)1-2(Ph); optionally substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R+, on the same substituent or different substituents, taken together with the atom(s) to which each R+ group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+ are selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, O(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O(halo C1-4 aliphatic), or halo(C1-4 aliphatic), wherein each of the foregoing C1-4aliphatic groups of R+ is unsubstituted.
  • The term "alkylidene chain" refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule, wherein one or more methylene units may optionally and independently be replaced with a group including, but not limited to, CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S; or NR.
  • As detailed above, in some embodiments, two independent occurrences of R° (or R+, or any other variable similarly defined herein), are taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Exemplary rings that are formed when two independent occurrences of R° (or R+, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R+, or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°)2, where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R+, or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of OR°
    Figure imgb0028
     these two occurrences of R° are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring:
    Figure imgb0029
     It will be appreciated that a variety of other rings can be formed when two independent occurrences of R° (or R+, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.
  • As described herein, a bond drawn from a substituent to the center of one ring within a multiple-ring system (as shown below), represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system. For example, Figure a represents possible substitution in any of the positions shown in Figure b.
    Figure imgb0030
  • This also applies to multiple ring systems fused to optional ring systems (which would be represented by dotted lines). For example, in Figure c, X is an optional substituent both for ring A and ring B.
    Figure imgb0031
  • If, however, two rings in a multiple ring system each have different substituents drawn from the center of each ring, then, unless otherwise specified, each substituent only represents substitution on the ring to which it is attached. For example, in Figure d, Y is an optionally substituent for ring A only, and X is an optional substituent for ring B only.
    Figure imgb0032
  • Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • The compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general scheme below, and the preparative examples that follow.
  • Figure imgb0033
  • Reagents and conditions: (a) i) LDA, toluene, ii) o-ClC4H6CH2SCN, toluene, 2 hours; (b) N2H4.H2O, EtOH, reflux, 16 hours.
  • Scheme I above shows a general synthetic route that is used for preparing the compounds 3 of this invention when R and Z are as described herein. Intermediates 2 may be prepared by methods substantially similar to those described in the literature by Davis and Cava J. Org. Chem. 1983, 48, 2774. Cyclisation of the malononitrile 2 with hydrazine hydrate furnishes the desired diamino-pyrazoles 3.
  • Figure imgb0034
  • Reagents and conditions: (a) EtOH (in the case of 4), i PrOH (in the case of 5), AcOHcat., microwave irradiation, 180°C, 15 minutes.
  • Scheme II above shows a general synthetic route that is used for preparing the compounds 6 of this invention when Z, R and R3 are as described herein. Pyrazolo[1,5-a]pyrimidines 6 are prepared by microwave assisted cyclisation of diamino-pyrazoles 3 with either a commercially available malonaldehyde 4 or its equivalent 5. Derivative 5 may be prepared by methods described by Coppola, et al, J. Het. Chem. 1974, 44, 51.
  • Table 1 below depicts exemplary compounds prepared according to the general methods described in Schemes I and II.
  • Figure imgb0035
    Figure imgb0036
  • Figure imgb0037
  • Reagents and conditions: (a) EtOH, AcOHcat., reflux, 3 hours; (b) ArB(OH)2, Pd(dppf)2Cl2, 2M Na2CO3, microwave irradiation, 120°C, 20 minutes.
  • Scheme III above shows a general synthetic route that has been used for preparing compounds 9 of this invention when Z, R and Ar are as described herein. Pyrazolo[1,5-a]pyrimidines 8 are prepared by cyclisation of diamino-pyrazoles 3 with the commercially available 2-bromo-malonaldehyde 7. Finally, the formation of the biaryl link derivatives 9 is achieved by treating bromides 8 with the desired boronic acid derivative in the presence of palladium(0) as a catalyst by using the microwave-assisted Suzuki coupling methods that are well known in the art. The reaction is amenable to a variety of substituted aryl or heteroaryl boronic acids.
  • Table 2 below depicts exemplary compounds prepared according to the general methods described in Scheme III.
  • Figure imgb0038
    Figure imgb0039
  • Figure imgb0040
  • Reagents and conditions: (a) DMF, 160°C, 10 hours; (b) DDQ, 1,4-dioxane, reflux, 2-3 hours.
  • Scheme IV above shows a general synthetic route that has been used for preparing compounds 12 of this invention when Z, R and R4 are as described herein. The cyclisation of diamino-pyrazoles 3 in presence of β-dimethylaminoketones 10 has been achieved by methods substantially similar to those described in the literature by Elnagdi and Erian Bull. Chem. Soc. Jpn 1990, 63, 1854. The reaction is amenable to a variety of diamino-pyrazoles 3 and β-dimethylaminoketones 10. Intermediates 11 are oxidized with DDQ according to step (b) of Scheme IV.
  • Table 3 below depicts exemplary compounds prepared according to the general methods described in Scheme IV.
  • Figure imgb0041
    Figure imgb0042
  • Reagents and conditions: (a) AcOH, reflux; (b) i) Protection conditions, ii) POCl3, 90°C; (c) i) H2, Pd/C, NaOAc, EtOH, ii) Deprotection conditions.
  • Scheme V above shows a general synthetic route that has been used for preparing compounds 16 of this invention when Z, R, R3 and R4 are as described herein. Intermediate 14 may be prepared by methods described by Sofon, et al, Pharmazie 1994, 49, 482 and by Ram, et al, Indian J. Chem. Sect. B 1995, 34, 514. After protection of amines of formula 14, derivatives 15 are obtained by a method well known to one of skill in the art. Finally, chloro derivatives 15 are reduced according to Scheme V step (c) i), and the amine is deprotected to afford compounds of structure 16.
  • Figure imgb0043
  • Reagents and conditions: (a) 1N NaOH, MeOH; (b) EDC, HOBt, DCM / DMF, HNR5V.
  • Scheme VI above shows a general method for preparing compounds of formula 19 of this invention when Z, R, R5 and V are as described herein. Each of the above steps is well known to one of skill in the art.
  • Table 4 below depicts exemplary compounds prepared according to the general methods described in Schemes VI.
  • Figure imgb0044
  • Other compounds prepared according to schemes and examples described herein are provided in Table 5:
    Figure imgb0045
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  • As discussed above, the present invention provides compounds that are inhibitors of protein kinases, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
  • As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • A method for the treatment or lessening the severity of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease, an Aurora family-mediated disease or a c-Met-mediated disease is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof. In certain embodiments of the present invention an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease, an Aurora family-mediated disease or a c-Met-mediated disease. The compounds and compositions, according the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease, an Aurora family-mediated disease or a c-Met-mediated disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.
  • The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
  • The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • As described generally above, the compounds of the invention are useful as inhibitors of protein kinases. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or a c-Met family kinase, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation of one or more of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met is implicated in the disease, condition, or disorder. When activation of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a "Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease", "an Aurora family-mediated disease" or "a c-Met-mediated disease" or disease symptom. Accordingly, the compounds of the present invention may be used in a method for treating or lessening the severity of a disease, condition, or disorder where activation or one or more of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met is implicated in the disease state.
  • The activity of a compound utilized in this invention as an inhibitor of a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met. Alternate in vitro assays quantitate the ability of the inhibitor to bind to a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with a Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, an Aurora family kinase or c-Met bound to known radioligands.
  • The term "measurably inhibit", as used herein means a measurable change in kinase activity between a sample comprising a compound of the invention and a kinase of interest and an equivalent sample comprising the kinase in the absence of said compound.
  • The term "Tec family tyrosine kinases-mediated condition", as used herein means any disease or other deleterious condition in which Tec family kinases are known to play a role. Such conditions include, without limitation, autoimmune, inflammatory, proliferative, and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • For example, Tec family tyrosine kinases -mediated conditions include diseases of the respiratory tract including, without limitation, reversible obstructive airways diseases including asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma airways hyper-responsiveness) and bronchitis. Additionally, Tec family tyrosine kinases diseases include, without limitation, those conditions characterised by inflammation of the nasal mucus membrane, including acute rhinitis, allergic, atrophic thinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis, sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia.
  • Tec family tyrosine kinases -mediated conditions also include diseases of the bone and joints including, without limitation, (pannus formation in) rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, and systemic sclerosis.
  • Tec family kinases-mediated conditions also include diseases and disorders of the skin, including, without limitation, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata and vernal conjunctivitis.
  • Tec family tyrosine kinases-mediated conditions also include diseases and disorders of the gastrointestinal tract, including, without limitation, Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g. migraine, rhinitis and eczema.
  • Tec family tyrosine kinases-mediated conditions also include those diseases and disorders of other tissues and systemic disease, including, without limitation, multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following angioplasty, tumours (for example leukemia, lymphomas), artherosclerosis, and systemic lupus erythematosus.
  • Tec family tyrosine kinases-mediated conditions also include allograft rejection including, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
  • According to another embodiment, the invention provides the use of one of the above-described pharmaceutical compositions in the manufacture of a medicament for treating or preventing an Aurora-mediated condition.
  • Preferably, that method is used to treat or prevent a condition selected from cancers such as cancers of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung, including lung adenocarcinoma and small cell lung cancer; stroke, diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease or disorder described above.
  • According to another embodiment, the invention relates to a method of inhibiting c-Met kinase activity in a biological sample in vitro comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • The term "c-Met-mediated disease" or "c-Met-mediated condition", as used herein, means any disease state or other deleterious condition in which c-Met is known to play a role. The terms "c-Met-mediated disease" or "c-Met-mediated condition" also mean those diseases or conditions that are alleviated by treatment with a c-Met inhibitor. Such conditions include, without limitation, renal, gastric, colon, brain, breast, prostate, and lung cancer, glioblastoma, atherosclerosis, lung fibrosis, conditions associated with organ transplantation, allergic disorders, and autoimmune disorders.
  • The term "c-Met" is synonymous with "cMet", "MET", "Met" or other designations known to one skilled in the art.
  • According to one embodiment, the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for treating or lessening the severity of renal, gastric, colon, brain, breast, prostate, and lung cancer, glioblastoma, atherosclerosis, lung fibrosis, conditions associated with organ transplantation, allergic disorders, or autoimmune disorders in a patient in need thereof.
  • In an alternative embodiment, the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for treating or lessening the severity of gastric or brain cancer in a patient in need thereof.
  • According to another embodiment, the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for treating or lessening the severity of renal cancer in a patient in need thereof.
  • According to yet another embodiment, the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for treating or lessening the severity of gastric cancer in a patient in need thereof.
  • Another aspect of the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for inhibiting tumor metastasis in a patient in need thereof.
  • The term "biological sample", as used herein, means a sample outside a living organism, and includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of protein kinase, e.g., inhibition of c-Met, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • Another embodiment of the present invention relates to the use of a compound of the present invention or composition thereof in the manufacture of a medicament for inhibiting protein kinase activity in a patient. Said protein kinases include, but are not limited to, the protein kinases listed above.
  • It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".
  • For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, For example, other therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention include surgery, radiotherapy (in but a few examples, gamma.-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), Gleevec™, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer therapies see, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999.
  • Other examples of agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singular®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
  • The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562 ; 5,886,026 ; and 5,304,121 . The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
    • EXAMPLES
  • As used herein, The term "Rt(min)" refers to the HPLC retention time, in minutes, associated with the compound. Unless otherwise indicated, the HPLC method utilized to obtain the reported retention time is as follows:
    • Column: Ace 5 C8, 15cm x 4.6mm id
    • Gradient: 0-100% acetonitrile+methanol (50:50) (20mM Tris phosphate at pH 7.0)
    • Flow rate: 1.5 ml/min
    • Detection: 225 nm
  • Example 1
    Figure imgb0222
  • 2-Pyridin-2-yl-malononitrile
  • To diisopropylamine (15.3 mL, 109 mmol) in toluene (500 mL), at 0-5°C, under nitrogen, was added drop wise over - 1/2 hour 1.6 M "BuLi / THE (68.5 mL, 109 mmol). The reaction mixture was stirred for a further 15 minutes before the drop wise addition of 2-pyridylacetonitrile (5.55 mL, 49.6 mmol) over 1 hour. 2-Chlorobenzylthiocyanate (20.0 g, 109 mmol), described in the literature by Schlesinger J. Am. Chem. Soc. 1954, 76, 585, was then added in solution in toluene (100 mL) over a period of 1 hour. The reaction mixture was stirred for an additional 2 hours. Water was added and the layers were separated. The organic phase was extracted twice with 200 mL 2N NaOH. The combined aqueous phases were cooled down to 0°C and acidified to ∼ pH 1. The precipitate obtained was filtered and dried to give the title compound as a pale tan solid (4.50 g, 63% yield). δH (DMSO-d6) 6.79 (1H, t), 7.09 (1H, d), 7.73 (1H, t), 7.79 (1H, dd), 12.95 (1H, br s).
  • Example 2
    Figure imgb0223
  • 4-Pyridin-2-yl-1H-pyrazole-3,5-diamine
  • A mixture of 2-pyridin-2-yl-malononitrile (0.65 g, 4.59 mmol) and hydrazine hydrate (225 µL, 4.59 mmol) in EtOH (5 mL) was heated to reflux and stirred for 16 hours. The reaction mixture was cooled down to room temperature and filtered. The resulting solid was washed with Et2O to provide the title compound as a light tan solid (0.42 g, 52%). The filtrate was evaporated to dryness and purified by silica gel chromatography eluting with NH4OH:MeOH:CH2Cl2 (0.5:5:95) to give a further 63.3 mg (8%) of the desired product. MS (ES+) 176, (ES-) 174. δH (DMSO-d6) 5.45 (4H, br s), 6.98 (1H, t), 7.57 (1H, d), 7.69 (1H, t), 8.46 (1H, d), 10.55 (1H, br s).
  • Example 3
    Figure imgb0224
  • 3-Pyridin-2-yl-6-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine I-1
  • A mixture of 4-pyridin-2-yl-1H-pyrazole-3,5-diamine (290 mg, 1.66 mmol) and 2-pyridin-4-yl-malonaldehyde (247 mg, 1.66 mmol) were placed in ethanol (5 mL) with a catalytic amount of acetic acid (6 drops). The reaction mixture was submitted to microwave irradiations at 140°C for 15 minutes. The crude mixture was cooled down to room temperature and the resulting precipitate was filtered and washed with more ethanol to provide the title as a golden yellow solid (295 mg, 62%). MS (ES+) 289, (ES-) 287. δH (DMSO-d6) 7.16 (1H, dd), 7.21 (2H, m), 7.84 (1H, m), 7.89 (2H, m), 8.57 (2H, br m), 8.65 (2H, d), 8.98 (1H, d), 9.44(1H, d).
  • A variety of other compounds have been prepared by methods substantially similar to those described herein Example 3. The characterization data for some of these compounds are summarized in Table 4 below and include HPLC, LC/MS (observed) and 1H NMR data.
  • 1H NMR data is summarized in Table 6 below wherein 1H NMR data was obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 1. Table 6. Characterization Data for Selected Compounds
    Cmpd # (I-) M+1(obs) Rt (min) 1H-NMR
    2 318 9.68 3.81 (3H, s), 7.07 (4H, m), 7.12 (1H, m), 7.75 (2H, d), 7.84 (1H, t), 8.54 (1H, m), 8.58 (1H, m) 8.82 (1H, d) 9.15 (1H, d)
    3 366 / (500 MHz) 7.14 (m, 3H), 7.46 (t, 1H), 7.60 (dd, 1H), 7.85 (m, 2H), 8.06 (m, 1H), 8.56 (m, 2H), 8.86 (d, 1H), 9.27 (d, 1H)
    4 318 / (500 MHz) 3.86 (s, 3H), 6.97 (m, 1H), 7.09 (s, 2H), 7.13 (m, 1H), 7.39 (m, 3H), 7.84 (m, 1H), 8.55 (m, 1H), 8.58 (d, 1H), 8.86 (d, 1H), 9.23 (d, 1H)
    5 302 10.12 2.40 (3H, s), 7.15 (3H, m), 7.35 (2H, d), 7.75 (2H, d), 7.90 (1H, t), 8.60 (2H, m), 8.90 (1H, s), 9.20 (1H, d)
    6 411 8.74 3.45 (3H, s), 7.20 (1H, m), 7.25 (2H, s), 7.90 (1H, t), 8.15 (1H, d), 8.35 (1H, d), 8.50 (1H, s), 8.55 (2H, m), 8.70 (1H, s), 9.20 (1H, d)
    7 289 8.76 7.20 (3H, m), 7.45 (1H, m), 7.90 (1H, t), 8.00 (1H, t), 8.15 (1H, d), 8.60 (2H, m), 8.70 (1H, m), 9.20 (1H, s), 9.45 (1H, s)
    8 290 8.29 7.20 (1H, m), 7.35 (2H, s), 7.90 (1H, t), 8.20 (1H, d), 8.60 (2H, m), 8.90 (1H, d), 9.25 (2H, dd), 9.65 (1H, s)
    9 290 8.44 7.20 (1H, m), 7.30 (2H, s), 7.95 (1H, t), 8.70 (3H, m), 8.80 (1H, s), 9.30 (1H,s), 9.45 (1H, s), 9.60 (1H, s)
    10 333 6.64 7.15 (1H, m), 7.25 (2H, s), 7.95 (1H, t), 8.05 (1H, d), 8.15 (1H, t), 8.40 (1H, d), 8.60 (2H, m), 9.30 (1H,s), 9.80 (1H, s)
    11 333 6.65 7.15 (1H, m), 7.25 (2H, d), 7.90 (1H, t), 8.25 (1H, d), 8.35 (1H, d), 8.60 (2H, m), 9.15 (1H, s), 9.25 (1H, s), 9.55 (1H, s)
    12 360 8.34 3.10 (6H, s), 7.15 (1H, m), 7.20 (1H, d), 7.55 (1H, d), 7.90 (1H, t), 8.05 (1H, t), 8.20 (1H, d), 8.60 (2H, m), 9.20 (1H, s), 9.45 (1H, s)
    13 402 8.26 3.60 (4H, m), 3.75 (4H, m), 7.15 (1H, m), 7.20 (1H, d), 7.60 (1H, d), 7.90 (1H, t), 8.00 (1H, t), 8.20 (1H, d), 8.60 (2H, m), 9.20 (1H, s), 9.45 (1H, s)
    14 360 808 3.05 (6H, s), 7.15 (1H, m), 7.25 (2H, s), 7.55 (1H, d), 7.90 (1H, t), 8.00 (1H, d), 8.20 (1H, d), 8.60 (2H, m), 8.75 (1H, s), 9.25 (1H, s), 9.50 (1H, s)
    15 402 8.06 3.65 (8H, m), 7.15 (1H, m), 7.25 (2H, s), 7.90 (1H, t), 8.00 (1H, d), 8.20 (1H, d), 8.60 (2H, m), 8.75 (1H, s), 9.20 (1H, s), 9.50 (1H, s)
    16 403 7.78 2.20 (6H, s), 2.45 (2H, m), 3.50 (2H, m), 7.15 (1H, m), 7.25 (2H, s), 7.50 (1H, t), 8.00 (1H, d), 8.10 (1H, t), 8.30 (1H, d), 8.60 (2H, m), 9.15 (1H, s), 9.45 (1H, s), 9.90 (1H, s)
    17 401 7.27 2.80 (4H, m), 3.40 (2H, m), 3.60 (2H, m), 7.15 (1H, m), 7.20 (2H, s), 7.50 (1H, d), 7.85 (1H, t), 8.05 (1H, t), 8.20 (1H, d), 8.60 (2H, m), 9.20 (1H, s), 9.45 (1H, s)
    18 401 7.22 3.30 (8H, m), 7.15 (1H, m), 7.20 (2H, br s), 7.90 (1H, t), 8.10 (1H, dd), 8.25 (1H, d), 8.65 (2H, m), 8.80 (1H, s), 9.30 (1H, s), 9.55 (1H, s)
    19 417 7.62 2.00 (3H, s), 2.20 (3H, s), 2.40 (2H, m), 3.00 (3H, s), 3.60 (2H, m), 7.15 (1H, m), 7.25 (2H, s), 7.90 (2H, m), 8.15 (1H, m), 8.55 (2H, m), 8.70 (1H, s), 9.20 (1H, s), 9.50 (1H, s)
    20 322 / (500 MHz) 7.11 (s, 2H), 7.14 (m, 1H), 7.56 (d, 2H), 7.83 (m, 1H), 7.86 (d, 2H), 8.55 (m, 1H), 8.57 (d, 1H), 8.85 (d, 1H), 9.24 (d, 1H)
    21 340 / (500 MHz) 7.18 (m, 1H), 7.28 (s, 2H), 7.85 (m, 1H), 7.89 (m, 2H), 8.15 (m, 2H), 8.59 (m, 1H), 8.63 (d, 1H), 9.40 (d, 1H), 9.69 (s, 1H), 9.78 (s, 1H)
    22 417 / (500 MHz) 3.25 (m, 2H), 3.55 (m, 2H), 3.62 (m, 2H), 3.8 (br, 2H), 4.05 (be, 2H), 4.43 (m, 2H), 7.16 (m, 3H), 7.80 (d, 2H), 7.85 (t, 1H), 8.56 (m, 2H), 8.83 (d, 1H), 9.16 (d, 1H)
    23 331 9.14 3.79 (3H, s), 3.97 (2H, s), 5.72 (2H, s), 7.02-7.04 (2H, m), 7.13 (1H, m), 7.21-7.25 (2H, m), 7.30-7.32 (2H, m), 7.66 (2H, d), 8.55 (1H, s), 8.95 (1H, s)
    24 302 8.17 3.96 (2H, s), 5.89 (2H, s), 7.15 (1H, m), 7.22-7.25 (2H, m), 7.31-7.32 (3H, m), 7.90 (1H, t), 8.00 (1H, m), 8.65 (1H, d), 8.97 (1H, s), 9.25 (1H, s)
    25 302 7.87 3.95 (2H, s), 5.94 (2H, s), 7.13 (1H, m), 7.21-7.25 (2H, m), 7.30-7.32 (2H, m), 7.81 (2H, d), 8.60 (2H, d), 8.73 (1H, s), 9.23 (1H, s)
  • Example 4
    Figure imgb0225
  • 6-Bromo-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine II-2
  • 4-(Pyridin-2-yl)-1H-pyrazole-3,5-diamine (2.54 g, 14.51 mmol) and 2-bromo-malonaldehyde (2.41 g, 15.97 mmol) were suspended in dry ethanol (35mL). A small amount of glacial acetic acid (30 drops) was added and the mixture was heated at reflux for 3 hours. After allowing the reaction to cool to room temperature the mixture was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with EtOAc containing 2% NH3(aq) solution to afford the title compound as a yellow solid (0.82 g, 19% yield). MS (ES+) 290/292. δH (DMSO-d6) 7.2 (3H, m), 7.9 (1H, t), 8.5 (1H, d), 8.6 (2H, m), 9.3 (1H, s).
  • Example 5
    Figure imgb0226
  • 4-(2-Amino-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-6-yl)-phenol II-6
  • 6-Bromo-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine (50mg, 0.17mmol) and 4-hydroxyphenylboronic acid (48 mg, 0.35 mmol) were suspended in dry DMF (1.4ml). Aqueous 2M Na2CO3 (0.346 mL, 0.69 mmol) was added and the reaction mixture was degassed. [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex in dichloromethane (1:1 ratio, 8mg, 0.010mmol) was added and the mixture was heated in a microwave at 120°C for 20 minutes. After allowing, the reaction to cool down to room temperature, the mixture was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with EtOAc to afford the title compound as a yellow solid (35 mg, 67% yield). MS (ES+) 304. δH (DMSO-d6) 6.8 (1H, d), 7.1 (3H, m), 7.2 (1H, d), 7.3 (1H, t), 7.9 (1H, t), 8.6 (2H, m), 8.8 (1H, s), 9.2 (1H, s), 9.7 (1H, s).
  • A variety of other compounds have been prepared by methods substantially similar to those described herein Example 5. The characterization data for some of these compounds are summarized in Table 5 below and include HPLC, LC/MS (observed) and 1H NMR data.
  • 1H NMR data is summarized in Table 7 below wherein 1H NMR data was obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 2.
  • Table 7. Characterization Data for Selected Compounds
    Cmpd # (II-) M+1(obs) Rt (min) 1H-NMR
    1 288 9.72 7.15 (3H, m), 7.90 (2H, m), 7.40 (1H, t), 7.50 (2H, m) 7.85 (3H, m), 8.55 (2H, m), 8.90 (1H, s), 9.25 (1H, s)
    3 322 10.14 7.15 (3H, m), 7.50 (1H, m), 7.65 (1H, m) 7.90 (1H, t), 8.60 (3H, m), 9.05 (1H, s)
    4 359 8.63 3.05 (6H, m), 7.15 (3H, m), 7.55 (1H, d), 7.90 (3H, m), 8.60 (2H, m), 8.90 (1H, s), 9.30 (1H, s)
    5 401 8.06 2.40 (4H, m), 3.20 (4H, m), 7.15 (2H, t), 7.70 (1H, d), 7.90 (3H, m), 8.60 (2H, m), 8.85 (2H, m), 8.90 (1H, s), 9.30 (1H, s)
    7 303 8.75 5.25 (2H, s), 6.60 (1H, d), 6.90 (2H, m), 7.10 (4H, m), 7.85 (1H, t), 8.55 (2H, m), 8.75 (1H, s), 9.05 (1H, s)
    8 402 8.60 2.20 (6H, s), 2.45 (2H, m), 3.40 (2H, m), 7.15 (3H, m), 7.85 (1H, t), 7.95 (4H, m), 8.60 (3H, m), 8.95 (1H, s), 9.30 (1H, s)
    9 416 8.71 2.00 (3H, s), 2.25 (3H, s), 2.40 (2H, m), 3.00 (4H, m). 3.55 (1H, m), 7.15 (3H, m), 7.50 (2H, d), 7.90 (3H, m), 8.60 (3H, m), 8.90 (1H, s), 9.30 (1H, s)
  • Example 6
    Figure imgb0227
  • 5-Phenyl-3-pyridin-2-yl-6,7-dihydro-pyrazolo[1,5-a]pyrimidin-2-ylamine
  • 6-Bromo-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine (0.52 g, 3.01 mmol) and 3-dimethylamino-1-phenyl-propan-1-one hydrochloride (0.64 g, 3.01 mmol) were suspended in dry DMF (10 mL). The mixture was heated at 160°C for 3 hours with stirring. After allowing the reaction to cool down to room temperature, the mixture was poured into cold water. The resulting precipitate was filtered and dried to afford the title compound as a yellow solid (0.79 g, 93% yield). MS (ES+) 290. δH (DMSO-d6) 3.3 (2H, m), 4.1 (2H, m), 6.1 (2H, s), 7.2 (1H, m), 7.7 (4H, m), 7.9 (1H, t), 8.2 (1H, m), 8.4 (1H, d), 8.6 (1H, d).
  • Example 7
    Figure imgb0228
  • 5-Phenyl-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine III-1 5-Phenyl-3-pyridin-2-yl-6,7-dihydro-pyrazolo[1,5-a]pyrimidin-2-ylamine (0.297 g, 1.03 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.256 g, 1.13 mmol) were suspended in dry 1,4-dioxane (10 mL). The mixture was heated at 110°C for 90 minutes. After allowing the reaction to cool to room temperature the mixture was concentrated under reduced pressure. The resulting solid was partitioned between ethyl acetate and 2M aqueous Na2CO3 solution. The organic layer was washed with further portions of 2M aqueous Na2CO3 solution (2 x 20mL), H2O (1 x 20), dried over Na2SO4, and filtered. Purification by silica gel chromatography eluting with EtOAc / petroleum ether (1 / 1) afford the title compound as a yellow solid (0.15 g, 51% yield). MS (ES+) 288. δH (DMSO-d6) 7.1 (3H, m), 7.6 (4H, m), 8.0 (1H, s), 8.4 (2H, d), 8.6 (1H, m), 8.8 (1H, d), 9.0 (1H, d).
  • A variety of other compounds have been prepared by methods substantially similar to those described herein Example 7. The characterization data for some of these compounds are summarized in Table 6 below and include HPLC, LC/MS (observed) and 1H NMR data.
  • 1H NMR data is summarized in Table 8 below wherein 1H NMR data was obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 3.
  • Table 8. Characterization Data for Selected Compounds
    Cmpd # (III-) M+1(obs) Rt (min) 1 H-NMR
    2 318 9.82 3.90 (3H, s), 7.05 (2H, m), 7.20 (3H, m), 7.50 (1H, d), 7.95 (1H, t), 8.30 (2H, d), 8.60 (1H, m), 8.80 (1H, d), 8.90 (1H, d)
  • Example 8
    Figure imgb0229
  • 2-Amino-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester IV-1
    A mixture of 4-(pyridin-2-yl)-1H-pyrazole-3,5-diamine (0.10 g, 0.57 mmol), (ethoxycarbonyl)malondialdehyde ( 0.084 g, 0.57 mmol) and 2 drops acetic acid in 1-propanol (3 mL) was heated in the microwave for 15 min at 180°C with stirring. The reaction was cooled down to room temperature and filtered, washing with ethanol and vacuum dried at 60°C for 3 days to provide the title compound as a brown solid (0.098 g, 61 % yield). MS (ES+) 284. δH (500 Mhz, DMSO-d6) 1.35 (3H, t), 4.36 (2H, q), 7.19 (1H, m), 7.36 (2H, s), 7.87 (1H, dt), 8.58 (2H, m), 8.82 (1H, d), 9.18 (1H, d).
  • Example 9
    Figure imgb0230
  • 2-Amino-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid IV-3
    A solution of 2-amino-3-pyridin-2-yl-pyrazolo[1,5-a]pyfimidine-6-carboxylic acid ethyl ester (1.58 g, 5.58 mmol) and potassium hydroxide (0.95 g, 16.7 mmol) in ethanol (30 mL) was refluxed for 3h, then cooled down to room temperature. The precipitate was filtered off, washed with ether, suspended in ether, treated with 2M HCI / Et2O (15 mL, 30 mmol) , stirred 0.5h, and filtered, washing with ether to provide an HCI salt of the title compound as a brown solid (0.88 g, 54 % yield). MS (ES+) 256. δH (500 Mhz, DMSO-d6) 7.25 (1H, m), 7.94 (1H, t), 8.56 (1H, d), 8.60 (1H, d), 8.83 (1H, d), 9.16 (1H, d).
  • Example 10
    Figure imgb0231
  • (2-Amino-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-6-yl)morpholin4-yl-methanone (IV-12)
  • A mixture of 2-amino-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.06 g, 0.20 mmol), morpholine (0.02 mL, 0.25 mmol) and HBTU (0.09 g, 0.25 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature under nitrogen for 24 hours. The precipitate was filtered off and purified by silica gel chromatography eluting with NH4OH : methanol : dichloromethane (0.5 : 5 : 95) to provide the title compound (0.02 g, 35% yield).). MS (ES+) 325. 8H (500 Mhz, DMSO-d6) 3.63 (8H, m), 7.17 (3H, m), 7.85 (1H, m), 8.52 (1H, s), 8.56 (2H, m), 8.99 (1H, s).
  • A variety of other compounds have been prepared by methods substantially similar to those described herein. The characterization data for some of these compounds are summarized in Table 7 below and include HPLC, LC/MS (observed) and 1H NMR data.
  • 1H NMR data is summarized in Table 9 below wherein 1H NMR data was obtained at 500 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 5. Table 9. Characterization Data for Selected Compounds
    Cmpd # (IV-) M+1(obs) Rt (min) 1H-NMR
    2 366 / (500 MHz) 1.70 (6H, m), 2.50 (6H, m), 3.34 (2H, m), 7.16 (1H, m), 7.23 (2H, s), 7.86 (1H, dt), 8.56 (2H, m), 8.61 (1H, t), 8.84 (1H, d), 9.19 (1H, d)
    4 382 / (500 MHz) 1.71 (2H, m), 2.35 (6H, m), 3.33 (2H, m), 3.58 (4H, m), 7.16 (1H, m), 7.23 (2H, s), 7.86 (1H, dt), 8.56 (3H, m), 8.85 (1H, d), 9.20 (1H, d)
    5 366 / (500 MHz) 1.49 (2H, m), 1.67 (2H, m), 1.92 (1H, m), 1.98 (1H, m), 2.15 (2H, m), 2.29 (3H, m), 3.00 (1H, m), 3.34 (2H, m), 7.16 (1H, m), 7.23 (2H, s), 7.86 (1H, dt), 8.57 (3H, m), 8.84 (1H, d), 9.19 (1H, d)
    6 368 / (500 MHz) 1.2 (6H, m), 2.50 (4H, m), 3.12 (5H, m), 3.75 (2H, m), 7.18 (3H, m), 7.85 (1H, m), 8.56 (3H, m), 9.05 (1H, m)
    7 326 / (500 MHz) 2.26 (3H, br s), 2.70 (2H, m), 3.05 (3H, br s), 3.49 (2H, m), 7.16 (3H, m), 7.84 (1H, dt), 8.54 (4H, m), 9.10 (1H, m)
    8 352 / (500 MHz) 1.07 (2H, m), 1.65 (3H, m), 2.46 (2H, m), 2.97 (2H, m), 3.17 (2H, m), 7.16, (1H, m), 7.23 (2H, s), 7.86 (1H, dt), 8.56 (3H, m), 8.86 (1H, d), 9.23 (1H, d)
    9 340 / (500 MHz) 1.72 (2H, m), 2.24 (6H, s), 2.41 (2H, t), 3.33 (2H, m), 7.17 (1H, m), 7.23 (2H, s), 7.86 (1H, dt), 8.56 (2H, m), 8.60 (1H, t), 8.84 (1H, d), 9.20 (1H, d)
    10 395 / (500 MHz) 1.70 (2H, m), 2.17 (3H, s), 2.36 (10H, m), 3.33 (2H, m), 7.16 (1H, m), 7.23 (2H, s), 7.56 (1H, dt), 8.56 (3H, m), 8.84 (1H, d), 9.20 (1H, d)
    11 338 / m), (500 MHz) 2.21 (3H, s), 2.36 (4H, 3.59 (4H, m), 7.16 (3H, m), 7.84 (1H, dt), 8.50 (1H, d), 8.55 (2H, m), 8.96 (1H, d)
    13 295 / m), (500 MHz,) 0.60 (2H, m), 0.74 (2H, 2.86 (1H, m), 7.16 (1H, m), 7.23 (2H, s), 7.85 (1H, dt), 8.55 (3H, m), 8.82 (1H, d), 9.18 (1H, d)
  • Example 11: Synthesis of Compounds According to Scheme VII
    Figure imgb0232
  • Reagents and conditions: (a) DMF-DMA, 85°C, 16 hours; (b) EtOH, AcOH, microwave irradiation, 120°C, 30 minutes.
  • Scheme VII above shows another general synthetic route that has been used for preparing compounds D of this invention when Z, R, R3 and R4 are as described herein. Intermediate B is prepared according to Scheme VII step (a) from Compound A. Pyrazolo[1,5-a]pyrimidines (D) are prepared by microwave assisted cyclization of diamino-pyrazoles C with enaminones B.
  • Exemplary compounds prepared according to the general methods described in Schemes VI and VII are shown below:
    Figure imgb0233
  • Example 12: Synthesis of 6-methyl-3-(6-(methylsulfinyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine
    Figure imgb0234
  • Synthesis of 4-chloro-6-(methylthio)pyrimidine
  • 4,6 Dichloropyrimidine (15.4 g, 0.10 mol) was dissolved in THF (120 mL) at room temperature and NaSMe (8.5g, 0.12 mol) was added as a solid. The reaction mixture was heated to 60 °C for 16 hours then let cool to room temperature and then diluted with ethyl acetate (300 mL) and water (300 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to an orange oil which was recrystalized from hexanes to give a pale yellow solid, 9.85 g, 0.061 mol, 61%. H NMR (500 MHz, CDCl3) 8.74 (s, 1H), 7.23 (s, 1H), 2.58 (s, 3H).
  • Synthesis of 2-(6-(methylthio)pyrimidin-4-yl)malononitrile
  • Sodium hydride (10.8 g, 0.27 mol) was suspended THF (100 mL) at 0 °C. To this suspension, a solution of malonitrile (8.0 g, 0.122 mol) in 50 mL THF was added dropwise. After the addition was complete the reaction mixture was stirred an additional 10 minutes and then 4-chloro-6-(methylthio)pyrimidine (9.85 g, 0.61 mol) was added in 50 mL THF. Nitrogen was bubbled through the reaction mixture for 10 min. and the Pd(PPh3)4 (3.3 g, 3.0 mmol) was added as a solid and the reaction mixture was heated to 60 °C. After heating for 4 hrs., the reaction mixture was let cool to room temperature and carefully quenched with water. The reaction mixture was then concentrated to a residue and 100 mL water added, followed by 6N HCI until the pH=1. A precipitate formed which was filtered, washed with water and diethyl ether, suspended in ethyl acetate (100 mL) and filtered again. This solid was dried to 11.4 g, 0.06 mol, 98%). %. H NMR (500 MHz, DMSO-d6) 8.28 (s, 1H), 6.47 (s, 1H), 2.58 (s, 3H).
  • Synthesis of 4-(6-(methylthio)pyrimidin-4-yl)-1H-pyrazole-3,5-diamine
  • 2-(6-(methylthio)pyrimidin-4-yl)malononitrile (11.4 g, 0.06 mol) was suspended in 150 mL EtOH and hydrazine hydrate (3 mL, 0.06 mol) was added. The reaction mixture was heated to reflux for 3 days. The reaction mixture was concentrated to a solid which was suspended in ethyl acetate (100 mL), and filtered. This solid was dried to give the product, 10.4 g, 46.8 mmol, 78%, ca. 80 % pure).
  • Synthesis of 6-methyl-3-(6-(methylsulfinyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine
  • 4-(6-(methylthio)pyrimidin-4-yl)-1H-pyrazole-3,5-diamine (1.0 g, 4.5 mmol) was combined with 3-ethoxy-2-methylacrylaldehyde (0.63 g, 5.3 mmol) in isopropanol (12 mL). Acetic acid (0.1 mL) was added to the reaction mixture which was then sealed in a microwave vessel and heated to 160 °C for 15 min. The reaction mixture was diluted with ethyl acetate (200 mL) and 1N NaOH (60 mL), the layers separated and the organic layer concentrated to 60 mL. This solution was cooled to 0 °C and 77% m-chloroperbenzoic acid (1.9 g, 8.5 mmol) was added. After 1 hr. a yellow precipitate formed which was filter off, washed with ethyl acetate and dried to give the product, 0.39 g, 30% yield. LCMS MH+ 289.29. H NMR (500 MHz, DMSO-d6) 9.02 (s, 1H) 8.91 (s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 7.14 (s, 2H), 2.91 (s, 3H), 2.34 (s, 3H).
  • Synthesis 1-(6-(2-amino-6-methylpyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide
  • 6-methyl-3-(6-(methylsulfinyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine (60 mg, 0.21 mmol) was dissolved in NMP with nipecotamide (100 mg, 0.78 mmol)and heated to 200 °C in a microwave for 20 min. The reaction mixture was purified by RP HPLC (C18, CH3CN/H2O 0.1 % TFA) and the pure fractions were poured into ethyl acetate/ 0.5 N NaOH. The organic phase was dried over sodium sulfate and concentrated to a yellow solid which was dissolved in 1N HCI in MeOH and concentrated to the HCI salt as a yellow solid, 20 mg, 0.052 mmol, 26 %. LC/MS MH+353.4
  • 1H NMR (500 MHz, DMSO-d6) 8.93 (s, 1H), 8.70 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 6.96 (s, 1H), 3.32 - 3.25 (m, 2H), 2.47 (m, 2H), 2.36 (s, 3H), 2.00 - 1.96 (m, 1H), 1.88 - 1.83 (m, 2H), 1.72 (m, 1H), 1.52 (s, 1H).
  • 1H NMR data is summarized in Table 10 below wherein 1H NMR data was obtained at 500 MHz in deuterated DMSO, unless otherwise indicated, and was found to be consistent with structure. Compound numbers correspond to the compound numbers listed in Table 5. Table 10. Characterization Data for Selected Compounds
    Cmpd # (V-) M+1(obs) Rt (min) 1H-NMR
    1 225.10 2.60 (500 MHz, dmso-d6) 8.59 (d, 1H), 7.81 (d, 2H), 7.40 (t, 2H), 7.19 (t, 1H), 6.65 (d, 1H), 2.45 (s, 3H) ppm
    2 265.90 2.62 1H NMR (500 MHz, DMSO-d6) d 9.20 (1 H, s), 8.81 (1 H, s), 7.72 (2 H, d), 7.05 (2 H, d), 6.70 (2 H, br s), 3.80 (3 H, s) ppm.
    3 348.20 2.10
    4 316.20 2.30
    5 356.10 2.30
    6 330.20 1.90
    7 302.20 2.20
    8 304.20 1.90
    9 316.20 2.30
    10 313.10 2.00
    11 332.10 1.80
    12 316.20 2.30
    13 306.10 2.10
    14 318.20 2.10
    15 364.10 2.50
    16 381.20 1.80
    17 372.10 2.20
    18 380.10 1.90
    19 372.10 2.40
    20 303.20 1.70
    21 333.10 2.00
    22 319.10 1.80
    23 345.20 1.50
    24 317.00 3.00 1H NMR (500 MHz, DMSO-d6) d 9.22 (1 H, s), 8.90 (1 H, s), 7.85 (2 H, d), 7.59 (2 H, d), 6.50 (2 H, br s), 4.30 (2 H, q), 1.30 (3 H, t) ppm.
    25 284.00 2.10 1H NMR (500 MHz, DMSO-d6) d 9.40 (1 H, s), 9.22 (1 H, s), 8.70 (1 H, d), 8.10 (1 H, d), 7.91 (1 H, dd), 7.40 (1 H, dd), 6.55 (2 H, br s), 4.30 (2 H, q), 1.30 (3 H, t) ppm.
    26 285.00 2.00 1H NMR (500 MHz, DMSO-d6) d 9.50 (1 H, s), 9.35 (1 H, s), 9.22(1 H, s), 8.85 (1 H, d), 8.65 (1 H, d), 6.60 (2 H, br s), 4.30 (2 H, q), 1.30 (3 H, t) ppm.
    27 285.00 1.90 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.30 (1 H, s), 9.25 (1 H, s), 8.90 (1 H, d), 8.21 (1 H, d), 6.62 (2 H, br s), 4.30 (2 H, q), 1.30 (3 H, t) ppm.
    28 257.00 1.50 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.20 (1 H, s), 9.00 (1 H, s), 8.80 (1 H, d), 8.15 (1 H, d), 6.80 (2 H, br s) ppm.
    29 330.60 3.41 H NMR (500 MHz, DMSO-d6) 9.03 (d, J = 2.3 Hz, 1H), 8.67 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.71 (s, 2H), 3.79 (s, 3H), 2.36 (s, 3H)
    30 378.70 3.90 H NMR (500 MHz, DMSO-d6) 9.09 (d, J = 2.3 Hz, 1H), 8.73 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 5.90 (s, 2H), 2.36 (s, 3H)
    31 378.60 3.41 H NMR (500 MHz, DMSO-d6) 8.03 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.1 Hz, 2H), 6.67 (m, 2H), 6.52 (m, 3H), 1.60 (s, 3H)
    32 382.30 2.50 1H NMR (500 MHz, DMSO-d6) d 9.65 (1 H, s), 9.25 (2 H, m), 8.9 (1 H, d), 8.20 (2 H, m), 7.45 (1 H, m), 7.20 (1 H, m), 7.05 (1 H, m), 6.70 (2 H, m), 4.60 (2 H, s) ppm.
    33 325.20 1.90 1H NMR (500 MHz, DMSO-d6) d 9.50 (1 H, s), 9.20 (1 H, m), 9.15 (1 H, s), 8.85 (1 H, d), 8.20 (1 H, m), 7.45 (1 H, m), 3.4 (3 H, m), 1.20 (6 H, d), 1.1 (3 H, m) ppm.
    34 393.40 1.40 1H NMR (500 MHz, DMSO-d6) d 9.60 (1 H, s), 9.25 (1 H, m), 9.20 (1 H, s), 8.85 (1 H, d), 8.20 (1 H, m),4.5 (1 H, m), 3.90 (1 H, m), 3.80 (1 H, m), 3.60 (2 H, m), 3.45 (1 H, m), 3.30 (1 H, m), 3.15 (1 H, m), 3.05 (1 H, m), 2.15 (1 H, m), 1.95 (2 H, m), 1.90 (4 H, m), 1.75 (2 H, m) ppm.
    35 417.40 1.60 1H NMR (500 MHz, DMSO-d6) d 9.60 (1 H, s), 9.21 (2 H, m), 8.89 (1 H, d), 8.20 (1 H, m),7.35 *3 H, m), 7.29 (2 H, m), 4.85 (2 H, s), 3.74 (2 H, m), 3.35 (2 H, m), 2.80 (6 H, s) ppm.
    36 375.40 1.30 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.21 (1 H, m), 8.89 (1 H, d), 8.80 (2 H, m), 8.20 (1 H, m),7.80 (2 H, m), 4.97 (2 H, s), 3.55 (2 H, m), 1.15 (3 H, t) ppm.
    37 390.40 1.90 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.21 (2 H, m), 8.85 (1 H, d), 8.20 (1 H, m), 7.30 (5 H, m), 4.80 (2 H, s), 4.0 (2 H, m), 3.50 (2 H, m) ppm.
    38 399.40 2.20 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.21 (2 H, m), 8.85 (1 H, d), 8.20 (1 H, m), 7.25 (5 H, m), 4.80 (2 H, s), 3.70 (2 H, m), 2.85 (2 H, m) ppm.
    39 340.30 1.50 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.21 (1 H, s), 9.20 (1 H, s), 8.85 (1 H, d), 8.20 (1 H, m), 3.55 (2 H, m), 3.35 (1 H, m), 1.95 (2 H, m), 1.90 (2 H, m), 1.70 (2 H, m) ppm.
    40 323.30 1.50 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.25 (2 H, m), 8.89 (1 H, d), 8.20 (1 H, m), 3.70 (2 H, m), 3.20 (3 H, s), 2.95 (2 H, m) ppm.
    41 360.40 2.10 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.25 (2 H, m), 8.89 (1 H, d), 8.20 (1 H, m), 7.30 (5 H, m), 4.70 (2 H, s), 3.0 (3 H, s) ppm.
    42 374.40 2.30 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.25 (2 H, m), 8.89 (1 H, d), 8.20 (1 H, m), 7.30 (5 H, m), 4.75 (2 H, s), 3.40 (2 H, m), 1.10 (3 H, t) ppm.
    43 389.40 1.50 1H NMR (500 MHz), DMSO-d6) d 9.60 (1 H, s), 9.22 (2 H, m), 8.89 (1 H, d), 8.20 (1 H, m), 8.0 (1 H, m), 7.20 (2 H, m), 6.75 (3 H, m), 4.45 (2 H, s), 2.90 (6 H, s) ppm.
    44 326.20 1.30 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.22 (2 H, m), 8.89 (1 H, d), 8.20 (1 H, m), 3.90 (2 H, m), 3.40 (1 H, m), 2.20 (1H, m), 1.95 (2 H, m) ppm.
    45 310.30 1.70 1H NMR (500 MHz, DMSO-d6) d 9.55 (1 H, s), 9.22 (2 H, m), 8.89 (1 H, d), 8.20 (1 H, m), 3.70 (2 H, m), 3.55 (2 H, m), 1.85 (4 H, m) ppm.
    46 376.40 2.00 1H NMR (500 MHz, DMSO-d6) d 9.60 (1 H, s), 9.30 (1 H, s), 9.25 (1 H, s), 8.89 (1 H, d), 8.40 (1 H, m), 8.20 (1 H, m), 7.30 (5 H, m), 5.20 (1 H, m), 3.75 (2 H, m) ppm.
    47 413.10 3.40 1H NMR (500 MHz, DMSO-d6) d 9.50 (1 H, s), 9.20 (1 H, s), 8.70 (1 H, t), 8.30 (1 H, t), 8.10 (1 H, d), 7.91 (1 H, t), 7.60 (2 H, m), 7.40 (1 H, d), 7.35 (1 H, d), 6.61 (2 H, s), 4.55 (2 H, m) ppm.
    48 307.10 2.15 1H NMR (500 MHz, DMSO-d6) d 8.79 (1 H, m), 8.46 (1 H, m), 6.32 (2 H, s), 4.30 (2 H, m), 4.05 (2 H, m), 2.69 (2 H, m), 2.0 (3 H, s), 1.91 (2 H, m), 1.29 (3 H, t) ppm.
    49 373.90 3.90
    50 319.20 1.70
    51 414.20 1.50
    52 290.00 1.30
    53 306.20 1.30
    54 402.40 1.40
    55 414.40 1.30
    56 394.10 2.50
    57 296.70 2.62
    58 280.90 3.22
    59 294.00 3.36
    60 451.40 0.80
    61 443.50 1.30
    62 403.40; 401.20 1,30; 1.90
    63 429.00 1.30
    64 458.40 1.80
    65 403.40 1.30
    66 444.40 1.70
    67 388.40 1.70
    68 459.40 1.30
    69 415.50 1.30
    70 429.40 1.30
    71 430.40 1.50
    72 384.40 1.70
    73 378.40 1.70
    74 430.20 1.50
    75 404.40 1.60
    76 472.50; 473.50 1.90; 1.30
    77 388.40 1.90
    78 445.40 1.30
    79 416.40 1.50
    80 431.50 1.50
    81 401.40 1.20
    82 444.40 1.60
    83 444.40 1.60
    84 469.50 1.30
    85 431.40 1.40
    86 372.30 1.60
    87 418.40 1.80
    88 445.50 1.40
    89 374.40 1.60
    90 413.40 1.70
    91 400.40 1.80
    92 418.40 1.60
    93 415.20 1.50
    94 389.40 0.80
    95 432.40 1.60
    96 402.40 1.50
    97 402.40 1.90
    98 388.40 1.70
    99 404.40 1.50
    100 451.40 1.40
    101 443.50 1.30
    102 429.40 1.30
    103 388.40 1.78
    104 415.40 1.30
    105 429.40 1.30
    106 384.40 1.80
    107 378.30 1.80
    108 404.40 1.80
    109 388.40 2.10
    110 431.50 1.60
    111 418.40 1.60
    112 416.40 1.60
    113 431.50 1.60
    114 399.40 1.60
    115 373.20 1.70
    116 413.40 1.70
    117 473.50 1.40
    118 345.90 2.09
    119 401.40 1.30
    120 389.40 1.40
    121 469.50 1.40
    122 431.50 1.50
    123 372.40 1.70
    124 445.50 1.40
    125 402.40 2.00
    126 402.40 2.00
    127 388.40 1.80
    128 404.40 1.50
    129 473.50 1.30
    130 403.40 1.30
    131 315.70 1.61 H NMR (500 MHz, DMSO-d6) 9.61 (d, J = 2.3 Hz, 1H), 8.95 (d, J = 2.3 Hz, 1H), 8.78 (dd, J = 5.1, 1.4 Hz, 2H), 8.13 (d, J = 6.3 Hz, 2H), 7.76 (d, J = 7.0 Hz, 2H), 7.57 (m, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.09 (br s, 2H).
    132 302.80 1.62 H NMR (500 MHz, DMSO-d6) 9.56 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 2.3 Hz, 1H), 8.79 (m, 2H), 8.49 (d, J = 8.3 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 6.1 Hz, 2H), 7.72 (dd, J = 8.4, 2.1 Hz, 1H), 2.33 (s, 3H).
    133 302.80 1.90 H NMR (500 MHz, DMSO-d6) 9.63 (d, J = 2.1 Hz, 1H), 9.13 (d, J = 2.1 Hz, 1H), 8.85 (d, J = 6.4 Hz, 2H), 8.46 (d, J = 5.1 Hz, 1H), 8.42 (s, 1H), 8.30 (d, J = 6.1 Hz, 2H), 7.08 (d, J = 4.5 Hz, 1H), 2.42 (s, 3H).
    134 395.00 1.67 H NMR (500 MHz, DMSO-d6) 9.60 (d, J = 2.2 Hz, 1H), 9.00 (d, J = 2.2 Hz, 1H), 8.85 (d, J = 6.6 Hz, 2H), 8.41 (d, J = 4.8 Hz, 1H), 8.30 (d, J = 6.5 Hz, 2H), 8.00 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.3, 5.3 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.33 (m, 3H), 5.30 (s, 2H).
    135 302.80 0.37 H NMR (500 MHz, DMSO-d6) 9.62 (d, J = 2.0 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 6.2 Hz, 2H), 8.70 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 6.9 Hz, 1H), 8.18 (d, J = 5.1 Hz, 2H), 7.74 (m, 1H), 2.43 (s, 3H).
    136 438.10 2.46 1H NMR (500 MHz, CDCl3) d 9.25 (2 H, m), 8.99 (1 H, s), 8.83 (1 H, d), 8.20 (1 H, s), 7.38 (1 H, d), 6.95 (1 H, d), 5.91 (2 H, s) ppm.
    137 367.20 2.00 500 MHz, MeOD, 7.82 (s, 1H), 7.49 (s, 1H), 7.25 (d, 2H), 7.11 (d, 1H), 7.78 (d, 2H), 6.18 (t, 1H), 5.80 (d, 1H)
    138 412.00 1.82
    139 444.40 1.80
    140 416.40 1.50
    141 444.50 1.60
    142 432.40 1.70
    143 358.40 1.40
    144 374.40 1.30
    145 387.50 1.30
    146 415.50 1.30
    147 371.20 1.50
    148 417.50 1.20
    149 415.50 1.30
    150 461.50 1.30
    151 373.40 1.20
    152 441.50 1.40
    153 469.50 1.40
    154 469.50 1.40
    155 403.40 1.40
    156 362.00 1.30
    157 375.40 1.10
    158 389.20 1.40
    159 375.40 1.20
    160 401.50 1.20
    161 412.50 1.10
    162 451.50 1.50
    163 464.20 1.20
    164 441.50 1.20
    165 387.40 1.10
    166 401.50 1.30
    167 444.20 1.60
    168 423.40 1.30
    169 415.50 1.10
    170 390.40 1.50
    171 346.30 1.30
    172 374.40 1.50
    173 417.50 1.40
    174 445.50 1.60
    175 469.50 1.50
    176 441.50 1.40
    177 469.50 1.40
    178 302.80 1.21 H NMR (500 MHz, DMSO-d6) 9.70 (d, J = 2.3 Hz, 1H), 9.13 (d, J = 2.3 Hz, 1H), 8.93 (d, J = 6.8 Hz, 2H), 8.50 (d, J = 6.8 Hz, 2H), 8.37 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 2.56 (s, 3H)
    179 373.00 1.46 H NMR (500 MHz, DMSO-d6) 9.64 (s, 1H), 9.16 (s, 1H), 8.84 (d, J = 5.1 Hz, 2H), 8.58 (s, 1H), 8.27 (d, J = 5.1 Hz, 2H), 7.59 (s, 1H), 3.73 (m, 4H), 1.65 (m, 6H)
    180 361.00 1.35 500 MHz, MeOD, 8.12 (d, 1H), 7.77 (d, 1H), 7.51 (d, 2H), 7.28 (s, 1H), 6.88 (d, 2H), 5.89 (s, 1H), 2.47 (m, 4H), 1.01 (t, 6H)
    181 319.30 1.19 DMSO, 500 MHz, 9.61 (s, 1H), 9.052 (s, 1H), 8.80 (d, 2H), 8.55 (s, 1H), 8.14 (d, 2H), 7.47 (s, 1H), 2.93 (s, 3H)
    182 347.30 1.37 DMSO, 500 MHz, 9.58 (s, 1H), 9.01 (s, 1H), 8.79 (d,2H), 8.52 (s, 1H), 8.08 (d, 2H), 7.46 (s, 1H), 4.15 (m, 1H), 1.19 (d, 6H)
    183 387.40 1.64 DMSO, 500 MHz, 9.56 (s, 1H), 9.01 (s, 1H), 8.78 (d, 2H), 8.51 (s, 1H), 8.10 (d, 2H), 7.47 (s, 1H), 1.91 (m, 2H), 1.86 (m, 2H), 1.62 (m, 1H), 1.30 (m, 6H)
    184 401.40 176 DMOS, 500 MHz, 9.58 (s, 1H), 9.01 (s, 1H), 8.77 (d, 2H), 8.50 (s, 1H), 8.11 (d, 2H), 7.48 (s, 1H), 3.20 (s, 2H), 1.69 (m, 6H), 1.18 (m, 3H), 0.96 (q, 2H)
    185 361.40 1.50 DMSO, 500 MHz, 9.59 (s, 1H), 9.13 (s, 1H), 8.81 (d, 2H), 8.56 (s, 1H), 8.18 (d, 2H), 7.50 (s, 1H), 3.21 (s, 2H), 1.89 (m, 1H), 0.94 (d, 6H)
    186 (400 MHz, DMSO-d6) 3.81(3H, s), 5.83(2H, br s), 7.05(2H, d), 7.21(1H, m), 7.43(2H, t), 7.71(2H, d), 7.86(2H, d), 8.69(1H, s) and 9.05(1H, s).
    187 (DMSO) 6.05 (2H, m, NH2), 7.25 (1H, m, ArH), 7.50 (2H, m, 4 x ArH), 7.90 (4H, m, 4 x ArH), 8.70 (2H, d, ArH x 2), 8.85 (1H, s, ArH), 9.40 (1H, s, ArH).
    188 (DMSO) 2.65 (1H, m), 2.91 (6H, br s), 2.97 (3H, s), 3.63 (1H, m), 3.80 (2H, m), 7.15 (1H, t), 7.60 (2H, d), 7.87 (1H, t), 7.92 (2H, d), 8.53-8.60 (2H, m), 8.92 (1H, s), 9.32 (1H, s), 9.40 (2H, br s).
    189 (DMSO) 2.69 (3H, s), 2.97 (3H, s), 3.54-3.80 (4H, m), 7.20 (1H, m), 7.48-7.61 (2H, m), 7.80-7.94 (3H, m), 8.45 (2H, br s), 8.54-8.58 (2H, m), 8.88 (1H, s), 9.28 (1H, s)
    190 416.60 3.73
    191 416.61 3.79 (DMSO) 1.91 (2H, m), 2.61 (2H, m), 2.96 (6H,m), 3.52 (2H, m), 7.15 (1H, t), 7.55 (2H, d), 7.86 (1H, t), 7.90 (2H, d), 8.39 (2H, br s), 8.57 (2H, m), 8.91 (1H, s), 9.32 (1H, s). (DMSO) 1.91-2.00 (2H, m), 2.58-2.64 (2H, m), 2.95-2.99 (3H, m), 3.49-3.54 (3H, br s), 3.64-3.74 (2H, m), 7.15 (1H, t), 7.55 (2H, d), 7.86 (1H, t), 7.90 (2H, d), 8.39 (2H, br s), 8.57 (2H, m), 8.91 (1H, s), 9.32 (1H,s).; (DMSO) 1.91 (2H, m), 2.61 (2H, m), 2.96 (6H, m), 3.52 (2H, m), 7.15 (1H, t), 7.55 (2H, d), 7.86 (1H, t), 7.90 (2H, d), 8.39 (2H, br s), 8.57 (2H, m), 8.91 (1H, s), 9.32 (1H, s)
    192 (DMSO) 1.38 (9H, s), 4.17 (2H, m), 7.08-7.15 (3H, m), 7.34 (2H, d), 7.48 (1H, m), 7.78 (2H, d), 7.84 (1H, t), 8.52-8.58 (2H, m), 8.85 (1H, s), 9.21 (1H, s)
    193 316.40 4.42 (DMSO) 7.16 (1H, t), 7.21 (2H, br s), 7.88 (1H, t), 8.01 (2H, d), 8.10 (2H, d), 8.56-8.60 (2H, m), 8.98 (1H, s), 9.40 (1H, s), 10.09 (1H, s).
    194 4.14 (DMSO) 4.55 (2H, d), 5.27 (1H, t), 7.10-7.18 (3H, m), 7.45 (2H, d), 7.79 (2H, d), 7.86 (1H, t), 8.54-8.60 (2H, m), 8.89 (1H, s), 9.23 (1H, s)
    195 317.44 3.72 (DMSO) 4.09 (2H, m), 7.19 (1H, t), 7.60 (2H, d), 7.88-7.92 (3H, m), 8.28 (2H, br s), 8.55-8.59 (2H, m), 8.92 (1H, s), 9.32 (1H, s).
    196 DMSO 7.15 (1H, t, ArH), 7.20 (2H, br s, NH2), 7.70 (1H, t, ArH), 7.90 (2H, d, ArH x 2), 8.20 (2H, d, ArH x 2), 8.60 (2H, m , ArH x 2), 8.95 ((1H, s, ArH), 9.40 (1H, s, ArH).
    197 DMSO 7.15 (1H, t, ArH), 7.70 (1H, t, ArH), 7.90 (2H, d, ArH x 2), 8.20 (1H, d, ArH), 8.35 (1H, s, ArH), 8.60 (2H, m , ArH x 2), 8.95 ((1H, s, ArH), 9.40 (1H, s, ArH).
    198 359.80 4.42 (DMSO) 2.9(2H, t), 3.6(2H, t), 7.1-7.3(6H, m), 7.9(1H,t), 8.5(2H, m), 8.8(1H, m), 8.9(1H, s), 9.2(1H, s)
    199 360.80 380 (DMSO) 4.3(2H,d), 5.0(NH2), 6.5(2H,d), 7.1(2H, d), 7.2(1H, m), 7.3(NH2), 7.9(1H, m), 8.5(2H, m), 8.9(NH), 9.0(1H, m), 9.3(1H, s)
    200 346.70 3.75 (DMSO) 4.6(2H, m), 7.2(1H, m), 7.3(NH2), 7.4(1H, m), 7.8(1H, m), 7.9 (1H, m), 8.4-8.7(4H, m), 8.9(1H, s), 9.2(1H, m), 9.3(NH)
    201 452.90 4.65 DMSO) 1.1(2H, m), 1.4(9H, m), 1.7(3H, m), 2.7(2H, m), 4.0(2H, m), 7.1(1H, m), 7.3(NH2), 7.9(1H, m), 8.4-8.6(3H, m), 8.9(1H, s0, 9.3(1H, s)
    202 317.44 3.82 (DMSO) 4.09-4.17 (2H, m), 7.20 (1H, t), 7.50 (1H, d), 7.58 (1H, t), 7.88 (1H, d), 7.91 (1H, t), 8.02 (1H, s), 8.40 (2H, br s), 8.58-8.62 (2H, m), 8.92 (1H, s), 9.29 (1H, s).
    203 336.44 4.85 (DMSO) 4.84 (2H, s), 7.11-7.17 (3H, m), 7.58 (2H, d), 7.82-7.86 (3H, m), 8.53-8.56 (1H, m), 8.58 (1H, d), 8.89 (1H, s), 9.27 (1H, s)
    204 269.70 3.50 (DMSO) 2.8(3H, d), 7.1(1H, m), 7.3(2H, brs), 7.9(1H, m), 8.5-8.7(3H, m), 8.9(1H, s), 9.2(1H, s)
    205 311.74 4.24 (DMSO) 0.9(6H, m), 1.9(1H, m), 3.1(2H, m), 7.1(1H, m), 7.2(NH2), 7.9(1H, t), 8.5-8.6(3H, m), 8.9(1H, s), 9.3(1H, s)
    206 338.75 3.30 (DMSO) 0.8(2H, m), 1.6(1H, m), 2.0(2H, m), 2.9(2H, m), 3.1-3.3(2H, m), 7.2(1H, m), 8.0(1H, m), 8.4(1H, m), 8.6(1H, m), 8.7(NH2), 8.9(1H, s), 9.2(1H, s)
    207 345.75 4.30 (DMSO) 4.6(2H, d), 7.2 (1H, m), (7.3, 2H, s), 7.4(3H, m), 7.9(1H, m), 8.5(2H, m), 8.9(1H, s), 9.2(1H, m), 9.3(NH, s)
    208 387.54 4.59 (DMSO) 2.40 (4H, m), 3.52 (2H, s), 3.59 (4H, t), 7.09-7.15 (3H, m), 7.45 (2H, d), 7.78 (2H, d), 7.84 (1H, t), 8.55 (1H, d), 8.59 (1H, d), 8.86 (1H, s), 9.22 (1H, s).
    209 (DMSO) 7.10 (3H, m, ARH, NH2), 7.25 (2H, m, ArH x 2), 7.40 (3H, m, ArH x 3), 7.60 (2H, m , ArH x 2), 7.85 (1H, t, ArH), 8.55 (2H, m, ArH x 2), 8.85 (1H, s, ArH), 9.10 (1H, s, ArH).
    210 336.42 4.85 (DMSO) 4.84 (2H, s), 7.12-7.17 (3H, m), 7.47-7.56 (2H, m), 7.81 (1H, d), 7.86 (1H, t), 7.91 (1H, s), 8.56 (1H, d), 8.59 (1H, d), 8.86 (1H, s), 9.24 (1H, s).
    211 1H NMR (DMSO) 2.55 (1H, m), 2.89 (4H, m), 3.02 (6H, br s), 3.82 (2H, br s), 3.96 (2H, s), 5.98 (2H, s), 7.14 (1H, m), 7.22-7.26 (2H, m), 7.31-7.32 (2H, m), 7.98 (1H, m), 8.14 (1H, m), 8.73 (1H, m), 9.01 (1H, m), 9.32 (1H, s)1H NMR (DMSO) 2.55 (1H, m), 2.89 (4H, m), 3.02 (6H, br s), 3.82 (2H, br s), 3.96 (2H, s), 5.98 (2H, s), 7.14 (1H, m), 7.22-7.26 (2H, m), 7.31-7.32 (2H, m), 7.98 (1H, m), 8.14 (1H, m), 8.73 (1H, m), 9.01 (1H, m), 9.32 (1H, s)
    212 DMSO 6.50 (1H, s, ArH), 7.10 (2H, s, NH2), 7.15 (1H, t, ArH), 7.40 (1H, d, ArH), 7.55 (2H, dd, ArH x 2), 7.85 (1H, t, ArH), 8.00 (1H, s, ArH), 8.50 (1H, m, ArH), 8.60 (1H, d, ArH), 8.90 (1H, s, ArH), 9.15 (1H, s, ArH).
    213 (DMSO) 3.00 (2H, s, CH2), 3.30 (2H, d, CH2), 6.95 (2H, s, NH2), 7.10 (1H, t, Arch), 7.30 (5H, m, ArH x 5), 7.80 (1H, t, ArH), 8.40 (1H, s, ArH), 8.50 (2H, m, ArH x 2), 8.70 (1H, s, ArH).
    214 345.52 4.30 (DMSO) 2.75 (6H, s), 4.32 (2H, s), 7.18 (1H, t), 7.68 (2H, d), 7.87-7.98 (3H, m), 8.55-8.60 (2H, m), 8.93 (1H, s), 9.34 (1H, s), 10.40 (2H, m).
    215 345.52 4.32 (DMSO) 2.75 (6H, d), 4.36 (2H, d), 7.25 (1H, t), 7.59 (1H, t), 7.61 (1H, t), 7.92-8.00 (2H, m), 8.13 (1H, s), 8.57 (1H, d), 8.60 (1H, d), 8.99 (1H, s), 9.38 (1H, s), 10.83 (2H, m).
    216 (DMSO) 2.65 (3H, s, CH3), 3.85 (3H, s, CH3), 7.10 (5H, m, ArH x 3, NH2), 7.50 (2H, d, ArH x 2), 7.85 (1H, t, ArH), 8.40 (1H, s, ArH), 8.55 (1H, d, ArH), 8.65 (1H, d, ArH).
    217 386.56 2.97 (DMSO) 2.56-2.65 (4H, m), 3.09-3.14 (4H, m), 3.61 (2H, s), 7.10-7.18 (2H, m), 7.43 (2H, d), 7.81 (2H, d), 7.85 (1H, t), 8.53-8.61 (3H, m), 8.88 (1H, s), 9.22 (1H, s).
    218 (DMSO) 3.85 (3H, s, CH3), 7.10 (2H, d, ArH x 2), 7.20 (1H, t, ArH ), 7.40 (4H, m, ArH x 2, NH2), 7.90 (1H, t, ArH), 8.50 (1H, s, ArH), 8.60 (2H, m, ArH x 2).
    219 1H NMR (DMSO) 3.81 (3H, s), 6.14 (2H, br s), 7.07 (2H, d), 7.74 (2H, d), 7.96 (2H, d), 8.53 (2H, d), 8.81 (1H, s), 9.14 (1H, s)
    220 332.73 3.73 (DMSO) 2.3(3H,s), 3.9(3H, s), 7.0(NH2), 7.1(2H, m), 7.6-7.8(3H, m), 8.3(1H, s), 8.4(1H, m), 8.8(IH, s), 9.2(1H s)
    221 318.42 3.22 4.60 (2H, s), 7.10-7.16 (3H, m), 7.38 (1H, d), 7.49 (1H, t), 7.68 (1H, d), 7.71 (1H, s), 7.85 (1H, t), 8.53-8.57 (1H, m), 8.59 (1H, d), 8.85 (1H, s), 9.19 (1H, s)
    222 (DMSO) 3.30 (4H, s, CH2 x 2), 3.50 (4H, s, CH2 x 2), 7.05 (1H, d, ArH), 7.15 (1H, d, ArH), 7.30 (1H, d, ArH ), 7.40 (2H, m, ArH x 2), 7.90 (1H, t, ArH), 8.55 (2H, m, ArH x 2), 8.75 (2H, s, NH2), 8.90 (1H, s, ArH), 9.25 (1H, s, ArH).
    223 386.52 3.05 (DMSO) 2.31-2.37 (4H, m), 2.70 (4H, t), 3.50 (2H, s), 7.08-7.13 (3H, m), 7.33 (1H, d), 7.46 (1H, t), 7.68-7.71 (2H, m), 7.83 (1H, t), 8.54-8.60 (2H, m), 8.83 (1H, s), 9.20 (1H, s).
    224 400.54 3.15 (DMSO) 1.68 (2H, m), 2.58 (2H, m), 2.64 (2H, m), 2.75 (2H, m), 2.80 (2H, m), 3.68 (2H, s), 7.10 (3H, m), 7.46 (2H, d), 7.76 (2H, d), 7.84 (1H, t), 8.54 (1H, d), 8.57 (1H, d), 8.86 (1H, s), 9.20 (1H, s)
    225 387.50 3.50 (DMSO) 2.39-2.43 (4H, m), 3.54 (2H, s), 3.59 (4H, t), 7.09-7.16 (3H, m), 7.37 (1H, d), 7.48 (1H, t), 7.68-7.73 (2H, m), 7.85 (1H, t), 8.56-8.60 (2H, m), 8.87 (1H, s), 9.22 (1H, s).
    226 (DMSO) 1.3-1.4(1H, m), 1.9-2.3(3H, m), 2.5-2.6(1H, m), 2.6-2.7(1H, m), 3.6-3.7(2H, m), 7.0-7.2(2.5H, m), 7.3-7.4(1H, m), 7.4-7.5(1H, m), 7.6-7.7(2H, m), 7.8-7.9(1H, m), 8.5-8.6(2H, m), 8.8-8.9(1H, s), 9.2(1H, s)
    227 (DMSO) 1.3-1.4(1H, m), 1.6-2.2(3H, m), 2.5-2.6(1H, m), 2.6-2.7(1H, m), 3.6-3.7(2H, m), 7.0-7.2(2.5H, m), 7.3-7.4(1H, m), 7.4-7.5(1H, m), 7.6-7.7(2H, m), 7.8-7.9(1H, m), 8.5-8.6(2H, m), 8.8-8.9(1H, s), 9.2(1H, s)
    228 (DMSO) 1.6-1.7(2H, m), 2.5-2.9(8H, m), 3.7(2H, m), 7.0-7.2(2.8H, m), 7.3-7.4(1H, m), 7.4-7.5(1H, m), 7.7(2H, m), 7.8-7.9(1H, m), 8.5-8.6(2H, m), 8.8-8.9(1H, s), 9.2(1H, s)
    229 (DMSO) 1.2-1.3(2H, m), 1.6-1.7(2H, m), 1.9-2.0(2H, m), 2.4-2.6(1H, m), 2.7-2.9(2H, m), 3.5-3.6(2H, m), 7.0-7.2(3H, m), 7.3(1H, m), 7.4-7.5(1H, m), 7.7-7.8(2H, m), 7.8-7.9(1H, m), 8.5-8.6(2H, m), 8.8(1H, m), 9.2(1H, m)
    230 (DMSO) 1.60 (2H, quin), 2.12 (3H, s), 2.27 (2H, br s), 2.38 (2H, t), 2.50 (3H, m), 3.49 (2H, s), 7.08-7.14 (3H, m), 7.40 (2H, d), 7.77 (2H, d), 7.85 (1H, t), 8.54-8.59 (2H, m), 8.86 (1H, s), 9.20 (1H, s).
    231 (DMSO) 1.40-1.48 (1H, m), 2.00-2.10 (1H, m), 2.22 (dd), 2.41-2.49 (2H, m), 2.58-2.69 (2H, m), 3.37-3.43 (2H, m), 3.58 (2H, d), 3.64 (2H, d), 7.09-7.15 (3H, m), 7.42 (2H, d), 7.75 (2H, d), 7.84 (1H, t), 8.53-8.59 (2H, m), 8.86 (1H, s), 9.21 (1H, s).
    232 (DMSO) 1.74-1.79 (2H, m), 2.22-2.28 (2H, m), 2.95 (2H, t), 3.36-3.40 (2H, m), 4.18-4.24 (2H, m), 7.09-7.20 (2H, m), 7.14 (1H, t), 7.62 (2H, d), 7.86 (1H, t), 8.93 (2H, d), 8.53-8.58 (2H, m), 8.89 (1H, s), 9.29 (1H, s).
    233 (DMSO) 1.40-1.48 (1H, m), 2.00-2.10 (1H, m), 2.22 (dd), 2.41-2.49 (2H, m), 2.58-2.69 (2H, m), 3.37-3.43 (2H, m), 3.58 (2H, d), 3.64 (2H, d), 7.09-7.15 (3H, m), 7.42 (2H, d), 7.75 (2H, d), 7.84 (1H, t), 8.53-8.59 (2H, m), 8.86 (1H, s), 9.21 (1H, s).
    234 (DMSO) 1.48-1.60 (2H, m),1.81-1.92 (2H, m), 1.97-2.08 (2H, m), 2.81-2.90 (1H, m), 2.95-3.09 (1H, m), 3.48-3.59 (2H, m), 7.10-7.18 (3H, m), 7.38-7.44 (2H, m), 7.75-7.89 (3H, m), 8.54-8.60 (2H, m), 8.88 (1H, br s), 9.22 (1H, br s).
    235 331.80 3.23 (DMSO) 7.0(NH2), 7.1(1H, m), 7.5-7.7(3H,m), 7.9(H, m), 8.0(2H, m), 8.5(2H, m), 8.7(1H, s), 9.4(1H, s), 10.7(NH)
    236 331.84 2.96 (DMSO) 1.37 (1H, s), 2.29 (3H, s), 3.70 (2H, s), 7.08-7.14 (3H, m), 7.43 (2H, d), 7.75 (2H, d), 7.85 (1H, t), 8.55 (1H, d), 8.58 (1H, d), 8.88 (1H, s), 9.20 (1H, s).
    237 294.73 3.22 (DMSO) 1.49 (6H, s), 5.54 (1H, s), 7.12-7.19 (3H, m), 7.85 (1H, t), 8.44 (1H, s), 8.50 (1H, d), 8.56 (1H, d), 9.01 (1H, s).
    238 266.63 2.95 (DMSO) 4.33 (2H, d), 5.43 (1H, t), 7.10-7.20 (3H, m), 7.82 (1H, t), 8.47-8.60 (3H, m), 9.09 (1H, s).
    239 286.69 9M (DMSO) 3.83 (3H, s), 7.08 (2H, d), 7.34 (2H, br s), 7.80 (2H, d), 9.08 (1H, s), 9.37 (1H, s)
    240 256.68 2.54 (DMSO) 3.79 (3H, s), 7.02 (2H, d), 7.64 (2H, d), 8.49 (1H, s), 8.84 (1H, s)
    241 381.40 1.59 DMSO, 500 MHz, 9.73 (s, 1H), 9.45 (s, 1H), 9.101 (s, 1h), 8.82 (d, 2H), 8.66 (s, 1H), 8.15 (d, 2H), 7.93 (s, 1H), 7.73 (d, 2H), 7.38 (t, 2H), 7.14 (t, 1H)
    242 411.40 1.56 DMSO, 500 MHz, 9.61 (s, 1H), 9.02 (s, 1H), 8.84 (d, 2H), 8.58 (s; 1H), 8.24 (d, 2H), 7.81 (s, 1H), 7.77 (d, 1H), 7.19 (t, 1H), 7.14 (d, 1H), 7.00 (t, 1H), 3.86 (s, 3H)
    243 375.40 1.56 DMSO, 500 MHz 9.61 (s, 1H), 9.12 (s, 1H), 8.80 (d, 2H), 8.55 (s,1H), 8.19 (d, 2H), 7.58 (s, 1H), 3.51 (m, 2H), 3.18 (s, 3H), 2.11 (m, 1H), 0.96 (d, 6H)
    244 375.40 1.52 DMSO, 500 MHz, 9.63 (s, 1H), 9.12 (s, 1H), 8.79 (d, 2H), 8.57 (s, 1H), 8.21 (d, 2H), 7.58 (s, 1H), 3.66 (m, 2H), 3.50 (m, 2H), 1.68 (q, 2H), 1.21 (t, 3H), 0.96 (t, 3H)
    245 362.40 1.40
    246 375.40 1.20
    247 463.20 1.30
    248 417.00 1.20
    249 461.50 1.20
    250 412.50 1.30
    251 388.40 1.40
    252 409.40 1.20
    253 444.50 1.60
    254 401.50 1.10
    255 451.50 1.40
    256 441.50 1.20
    257 374.40 1.30
    258 358.40 1.30
    259 372.20 1.40
    260 430.50 1.40
    261 441.50 1.50
    262 388.40 0.70
    263 423.20 1.30
    264 464.20 1.30
    265 441.50 1.20
    266 417.20 1.30
    267 401.50 1.20
    268 386.20 1.30
    269 415.50 1.30
    270 402.50 1.30
    271 416.50 1.30
    272 364.50 1.30
    273 284.30; 284.40 1.61; 1.53 H NMR (500 MHz, DMSO-d6) 8.71 (s, 1H), 8.37 (d, J = 1.6 Hz, 2H), 7.45 (s, 1H), 7.20 (s, 1H), 6.89 (s, 2H), 4.10 - 4.07 (m, 1H), 2.30 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H).
    274 347.80 2.55
    275 399.70 2.86
    276 310.30; 310.44 1.80 H NMR (500 MHz, DMSO-d6) 8.90 (m, 2H), 8.65 (s, 1H), 8.52 (d, J = 1.7 Hz, 1H), 3.81 (m, 4H), 2.35 (s, 3H), 1.69 (m, 2H), 1.63 (m, 4H).
    277 296.30 1.80
    278 326.30 1.60
    279 318.30 1.90
    280 245.70 2.20
    281 273.40 2.73 DMSO, 500 MHz, 8.70 (s, 2H), 8.48 (d, 1H), 8.31 (s, 1H), 2.59 (s, 3H), 2.31 (s, 3H)
    282 298.50 1.95 H NMR (500 MHz, CDCl3) 9.93 (brs, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 3.69 - 3.67 (m, 1H), 2.43 (s, 3H), 1.85 - 1.68 (m, 2H), 1.40 (d, J = 6.5 Hz, 3H), 1.05 (t, J = 7.4 Hz, 3H),
    283 300.28 1.41 H NMR (500 MHz, MeOD) 8.65 (s, 1H), 8.55 (s, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 7.15 (brs, 1H), 4.29 (brs, 1H), 3.67-3.60 (m, 2H), 2.40 (s, 3H), 1.29 (d, J = 6.7 Hz, 3H)
    284 339.36 1.19
    285 415.44 1.51 H NMR (500 MHz, MeOD) 8.67 (s, 1H), 8.63 (s, H), 8.52 (s, 1H),) 7.54 - 7.50 (m, 5H), 7.07 (s, 1H), 4.34 (s, 2H), 3.61 (m, 2H), 3.33 - 3.30 (m, 2H), 2.40 (s, 3H), 2.33 (m, 2H), 2.31 (m, 1H), 1.91 (m, 2H)
    286 401.44 1.48 H NMR (500 MHz, MeOD) 8.67 (s, 1H), 8.63 (s, H), 8.52 (s, 1H), 8.51 (s, 1H), 7.54 - 7.50 (m,5H), 7.07 (s, 1H), 3.61 (m, 2H), 3.33 - 3.30 (m, 2H), 2.40 (s, 3H), 2.33 (m, 2H), 2.31 (m, 1H), 1.91 (m, 2H)
    287 314.13 1.52 H NMR (500 MHz, MeOD) 8.66 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.51 (1H), 7.27 (s, 1H), 4.38 (m, 1H), 3.71-3.62 (,m, 2H), 2.65 (s, 3H),1.62 - 1.59 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H)
    288 314.40 1.69 H NMR (500 MHz, MeOD) 8.65 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 7.19 (s, 1H), 3.72- 3.62 (m, 2H), 2.40 (s, 3H), 2.2.02 (d, J = 10.5 Hz, 1H), 1.80 - 1.75 (m, 1H), 1.64 -1.58 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H)
    289 282.30 1.60
    290 296.30 1.70
    291 324.30 2.00
    292 314.30 1.60
    293 300.30 1.40
    294 298.30 1.80
    295 300.30 1.40
    296 312.30 2.00 H NMR (500 MHz, DMSO-d6) 8.84 (s, 2H), 8.53 (s, 1H), 8.47 (s, 1H),2.34 (m, 4H), 1.81 (d, J = 6.6 Hz, 1H), 1.14 - 1.11 (m, 3H), 0.90 (m, 6H).
    297 352.40 2.30
    298 342.30 1.80
    299 310.40 1.73
    300 346.40 2.17
    301 346.40 2.21
    302 340.30 2.70
    303 372.40 3.30
    304 400.40 3.70
    305 379.40 2.70
    306 326.30 2.20
    307 390.40 3.20
    308 374.30 1.90
    309 353.40 1.90; 1.40 H NMR (500 MHz, DMSO-d6) 8.93 (s, 1H), 8.70 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 6.96 (s, 1H), 3.32 - 3.25 (m, 2H), 2.47 (m, 2H), 2.36 (s, 3H), 2.00 - 1.96 (m, 1H), 1.88 - 1.83 (m, 2H), 1.72 (m, 1H), 1.52 (s, 1H).
    310 270.10 1.30
    311 323.40 1.12
    312 337.20 1.20
    313 339.40 0.90
    314 337.42 0.90
    315 366.50 1.00
    316 297.30 1.00
    317 339.40 1.30
    318 311.40 1.10
    319 325.40 1.20
    320 353.50 1.30
    321 382.50 1.10
    322 309.20 1.20
    323 351.50 1.40
    324 323.20 1.30
    325 339.40 1.00
    326 327.40 1.10
    327 311.40 1.90
    328 355.40 1.20
    329 353.40 1.20
    330 409.50 1.40
    331 380.50 1.10
    332 310.30 1.90
    333 336.40 2.10
    334 416.50 2.20
    335 312.30 1.50
    336 416.50 2.20
    337 311.43 1.48 H NMR (500 MHz, DMSO-d6) 8.80 (s, 1H), 8.55 (s, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.09 (m, 3H), 7.35 (s, 1H), 3.99 (m, 1H), 3.81 (m, 1H), 3.79-3.58 (m, 2H), 2.32 (s, 3H), 2.19 - 2.13 (m, 1H), 1.93 - 1.87 (m, 1H).
    338 409.50 1.80
    339 324.30 2.00
    340 340.30 1.60
    341 353.40 1.40
    342 326.30 1.50
    343 407.40 1.68
    344 353.40 1.50
    345 270.30 1.50
    346 339.30 1.30
    347 312.30 1.40
    348 395.10 1.70
    349 296.30 1.70
    350 373.30 1.50
    351 346.20 1.50
    352 429.40 1.90
    353 373.30 1.50
  • Example 13: ITK Inhibition Assay (Radiometric)
  • Compounds are screened for their ability to inhibit Itk using a radioactive-phosphate incorporation assay. Assays are carried out in a mixture of 100 mM HEPES (pH 7.5), 10mM MgCl2, 25mM NaCl, 0.01 % BSA and 1mM DTT. Final substrate concentrations are 15 µM [γ-33P]ATP (400mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 2µM peptide (SAM68 protein D332-443). Assays are carried out at 25 °C. in the presence of 30 nM Itk. An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 50 µL of the stock solution is placed in a 96 well plate followed by addition of 1.5µL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15µM with 2-fold serial dilutions) in duplicate (final DMSO concentration 1.5%). The plate is pre-incubated for 10 minutes at 25°C and the reaction initiated by addition of 50µL [γ-33P]ATP (final concentration 15µM).
  • The reaction is stopped after 10 minutes by the addition of 50µL of a TCA / ATP mixture (20% TCA, 0.4mM ATP). A Unifilter GF/C 96 well plate (Perkin Elmer Life Sciences, Cat no. 6005174) is pretreated with 50µL Milli Q water prior to the addition of the entire reaction mixture (150 µL). The plate is washed with 200µL Milli Q water followed by 200mL of a TCA / ATP mixture (5% TCA, 1mM ATP). This wash cycle is repeated a further 2 times. After drying, 30µL Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) is added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
  • IC50 data are calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1mM DTT. Final substrate concentrations in the assay are 7.5 µM [γ-33P]ATP (400mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 3µM peptide (SAM68 protein D332-443). Assays are carried out at 25°C in the presence of 50 nM Itk. An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 50 µL of the stock solution is placed in a 96 well plate followed by addition of 2µL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 50µM with 2-fold serial dilutions) in duplicate (final DMSO concentration 2%). The plate is pre-incubated for 10 minutes at 25°C and the reaction initiated by addition of 50µL [γ-33P]ATP (final concentration 7.5µM).
  • The reaction is stopped after 10 minutes by the addition of 100mL 0.2M phosphoric acid + 0.01% TWEEN 20. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHNOB50) is pretreated with 100µL 0.2M phosphoric acid + 0.01% TWEEN 20 prior to the addition of 170mL of the stopped assay mixture. The plate is washed with 4 x 200µL 0.2M phosphoric acid + 0.01% TWEEN 20. After drying, 30µL Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) is added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
  • Ki(app) data are calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • Example 14: ITK Inhibition Assay (UV)
  • Compounds are screened for their ability to inhibit Itk using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249).
  • Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA,1mM DTT, 2.5 mM phosphoenolpyruvate, 300 µM NADH, 30 µg/ml pyruvate kinase and 10 µg/ml lactate dehydrogenase. Final substrate concentrations in the assay are 100µM ATP (Sigma Chemicals) and 3µM peptide (Biotinylated SAM68 D332-443). Assays are carried out at 25°C and in the presence of 100nM Itk.
  • An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 60 µl of the stock solution is placed in a 96 well plate followed by addition of 2 µl of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15µM). The plate is preincubated for 10 minutes at 25°C and the reaction initiated by addition of 5 µl of ATP. Initial reaction rates are determined with a Molecular Devices SpectraMax Plus plate reader over a 10 minute time course. IC50 and Ki data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • In general, compounds of the invention, including compounds in Table 1, are effective for the inhibition of ITK.
  • Example 15: BTK Inhibition Assay
  • Compounds are screened for their ability to inhibit Btk using a radioactive-phosphate incorporation assay at Vertex Pharmaceuticals. Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1mM DTT. Final substrate concentrations in the assay are 50µM [γ-33P]ATP (200mCi 33P ATP/ mmol ATP, Amersham Pharmacia Biotech, Amersham, UK / Sigma Chemicals) and 2µM peptide (SAM68 D332-443). Assays are carried out at 25°C and in the presence of 25 nM Btk. An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of the peptide and the test compound of interest. 75 µL of the stock solution is placed in a 96 well plate followed by addition of 2µL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15µM) in duplicate (final DMSO concentration 2%). The plate is preincubated for 15 minutes at 25°C and the reaction initiated by addition of 25µL peptide (final concentration 2µM). Background counts are determined by the addition of 100mL 0.2M phosphoric acid + 0.01% TWEEN to control wells containing assay stock buffer and DMSO prior to initiation with peptide.
  • The reaction is stopped after 10 minutes by the addition of 100mL 0.2M phosphoric acid + 0.01% TWEEN. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) is pretreated with 100µL 0.2M phosphoric acid + 0.01% TWEEN 20 prior to the addition of 170mL of the stopped assay mixture. The plate is washed with 4 x 200µL 0.2M phosphoric acid + 0.01% TWEEN 20. After drying, 30µL Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) is added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
  • After removing mean background values for all of the data points, Ki(app) data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • Compounds are screened for their ability to inhibit Btk using an AlphaScreen™ phosphotyrosine assay at Vertex Pharmaceuticals. Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1mM DTT. Final substrate concentrations in the assay are 50µM ATP (Sigma Chemicals) and 2µM peptide (Biotinylated SAM68 D332-443). Assays are carried out at 25 °C and in the presence of 25 nM Btk. An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of peptide and the test compound of interest. 37.5µL of the stock solution is placed in each well of a 96 well plate followed by 1µL of DMSO containing serial dilutions of the test compound (typically starting from a final concentration of 15µM) in duplicate (final DMSO concentration 2%). The plate is preincubated for 15 minutes at 25°C and the reaction initiated by addition of 12.5µL peptide (final concentration 2µM). Background counts are determined by the addition of 5µL 500mM EDTA to control wells containing assay stock buffer and DMSO prior to initiation with Biotin-SAM68.
  • The reaction is stopped after 30 minutes by diluting the reaction 225-fold into MOPS buffer (20mM MOPS (pH 7.0), 1mM DTT, 10mM MgCl2, 0.1% BSA) containing 50mM EDTA to bring the final concentration of peptide to 9nM.
  • AlphaScreen™ reagents are prepared according to the manufacturers instructions (AlphaScreen™ phosphotyrosine (P-Tyr-100) assay kit, PerkinElmer catalogue number 6760620C). Under subdued lighting, 20µL of AlphaScreen™ reagents are placed in each well of a white half area 96 well plate (Corning Inc. - COSTAR 3693) with 30µL of the stopped, diluted kinase reactions. Plates are incubated in the dark for 60 minutes prior to reading on a Fusion Alpha plate reader (PerkinElmer).
  • After removing mean background values for all of the data points, Ki(app) data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • In general, compounds of the invention, including compounds in Table 1, are effective for the inhibition of Btk.
  • Example 16: RLK Inhibition Assay
  • Compounds are screened for their ability to inhibit Rlk using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays are carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1mM DTT. Final substrate concentrations in the assay are 100µM ATP (Sigma Chemicals) and 10µM peptide (Poly Glu:Tyr 4:1). Assays are carried out at 30 °C and in the presence of 40nM Rlk. Final concentrations of the components of the coupled enzyme system are 2.5 mM phosphoenolpyruvate, 300 µM NADH, 30 µg/ml pyruvate kinase and 10 µg/ml lactate dehydrogenase.
  • An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 60 µl of the stock solution is placed in a 96 well plate followed by addition of 2 µl of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 7.5µM). The plate is preincubated for 10 minutes at 30°C and the reaction initiated by addition of 5 µl of ATP. Initial reaction rates are determined with a Molecular Devices SpectraMax Plus plate reader over a 10 minute time course. IC50 and Ki data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • In general, compounds of the invention, including compounds in Table 1, are effective for the inhibition of RLK.
  • Example 17: JAK3 Inhibition Assays
  • Compound inhibition of JAK is assayed by the method described by G. R. Brown, et al, Bioorg. Med. Chem. Lett. 2000, vol. 10, pp 575-579 in the following manner. Into Maxisorb plates, previously coated at 4°C with Poly (Glu, Ala, Tyr) 6:3:1 then washed with phosphate buffered saline 0.05% and Tween (PBST), is added 2 µM ATP, 5 mM MgCl2, and a solution of compound in DMSO. The reaction is started with JAK enzyme and the plates incubated for 60 minutes at 30°C. The plates are then washed with PBST, 100 µL HRP-Conjugated 4010 antibody is added, and the plate incubated for 90 minutes at 30°C. The plate is again washed with PBST, 100 µL TMB solution is added, and the plates are incubated for another 30 minutes at 30°C. Sulfuric acid (100 µL of 1M) is added to stop the reaction and the plate is read at 450 nm to obtain the optical densities for analysis to determine Ki values.
  • Compound inhibition of JAK may also be assayed in the following manner: Compounds are screened for their ability to inhibit JAK3 using the assay shown below. Reactions are carried out in a kinase buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM MgCl2, 25 mM NaCl, and 0.01% BSA. Substrate concentrations in the assay are 5 µM ATP (200 uCi/µmole ATP) and 1 µM poly(Glu)4Tyr. Reactions are carried out at 25 °C and 1 nM JAK3. To each well of a 96 well polycarbonate plate is added 1.5 µl of a candidate JAK3 inhibitor along with 50 µl of kinase buffer containing 2 µM poly(Glu)4Tyr and 10 µM ATP. This is then mixed and 50µl of kinase buffer containing 2 nM JAK3 enzyme is added to start the reaction. After 20 minutes at room temperature (25C), the reaction is stopped with 50µl of 20% trichloroacetic acid (TCA) that also contained 0.4 mM ATP. The entire contents of each well are then transferred to a 96 well glass fiber filter plate using a TomTek Cell Harvester. After washing, 60 µl of scintillation fluid is added and 33P incorporation detected on a Perkin Elmer TopCount.
  • In general, compounds of the invention, including compounds in Table 1, are effective for the inhibition of JAK (e.g., JAK-3).
  • Example 18: Aurora B (Aurora-1) Inhibition Assay
  • An assay buffer solution is prepared which consists of 25 mM HEPES (pH 7.5), 10 mM MgCl2, 0.1% BSA and 10% glycerol. A 22 nM Aurora-B solution, also containing 1.7 mM DTT and 1.5 mM Kemptide (LRRASLG), is prepared in assay buffer. To 22 µL of the Aurora-B solution, in a 96-well plate, is added 2 µl of a compound stock solution in DMSO and the mixture is allowed to equilibrate for 10 minutes at 25°C. The enzyme reaction is initiated by the addition of 16 µl stock [γ-33P]-ATP solution (-20 nCi/µL) prepared in assay buffer, to a final assay concentration of 800 µM. The reaction is stopped after 3 hours by the addition of 16 µL 500 mM phosphoric acid and the levels of 33P incorporation into the peptide substrate is determined by the following method.
  • A phosphocellulose 96-well plate (Millipore, Cat no. MAPHNOB50) is pretreated with 100 µL of a 100 mM phosphoric acid prior to the addition of the enzyme reaction mixture (40 µL). The solution is left to soak on to the phosphocellulose membrane for 30 minutes and the plate subsequently is washed four times with 200 µL of a 100 mM phosphoric acid. To each well of the dry plate is added 30 µL of Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac). Levels of non-enzyme catalysed background radioactivity are determined by adding 16 µL of the 500 mM phosphoric acid to control wells, containing all assay components (which acts to denature the enzyme), prior to the addition of the [γ-33P]-ATP solution. Levels of enzyme catalysed 33P incorporation are calculated by subtracting mean background counts from those measured at each inhibitor concentration. For each Ki determination 8 data points, typically covering the concentration range 0 -10 µM compound, are obtained in duplicate (DMSO stocks are prepared from an initial compound stock of 10 mM with subsequent 1:2.5 serial dilutions). Ki values are calculated from initial rate data by non-linear regression using the Prism software package (Prism 3.0, Graphpad Software, San Diego, CA).
  • Example 19: Aurora-A (Aurora-2) Inhibition Assay
  • Compounds are screened for their ability to inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays are carried out in a mixture of 100mM Hepes (pH7.5), 10mM MgCl2, 1mM DTT, 25mM NaCl, 2.5mM phosphoenolpyruvate, 300 µM NADH, 30 µg/ml pyruvate kinase and 10 µg/ml lactate dehydrogenase. Final substrate concentrations in the assay are 400µM ATP (Sigma Chemicals) and 570µM peptide (Kemptide, American Peptide, Sunnyvale, CA). Assays are carried out at 30 °C and in the presence of 40nM Aurora-2.
  • An assay stock buffer solution is prepared containing all of the reagents listed above, with the exception of Aurora-2 and the test compound of interest. 55 µl of the stock solution is placed in a 96 well plate followed by addition of 2 µl of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 7.5µM). The plate is preincubated for 10 minutes at 30°C and the reaction initiated by addition of 10 µl of Aurora-2. Initial reaction rates are determined with a Molecular Devices SpectraMax Plus plate reader over a 10 minute time course. IC50 and Ki data are calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).
  • Example 20: c-Met Inhibition Assay
  • Compounds are screened for their ability to inhibit c-Met kinase activity using a standard coupled enzyme system (Fox et al., Protein Sci. 1998, 7, 2249). Reactions are carried out in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 300 µM NADH, 1 mM DTT, and 1.5% DMSO. Final substrate concentrations in the assay are 200 µM ATP (Sigma Chemicals, St Louis, MO) and 10 µM polyGluTyr (Sigma Chemical Company, St. Louis). Reactions are carried out at 30°C and 80 nM c-Met. Final concentrations of the components of the coupled enzyme system are 2.5 mM phosphoenolpyruvate, 300 µM NADH, 30 µg/ml pyruvate kinase and 10 µg/ml lactate dehydrogenase.
  • An assay stock buffer solution is prepared containing all of the reagents listed above with the exception of ATP and a test compound of the present invention. The assay stock buffer solution (175 µl) is incubated in a 96 well plate with 5 µl of the test compound of the present invention at final concentrations spanning 0.006 µM to 12.5 µM at 30 °C for 10 minutes. Typically, a 12-point titration is conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds of the present invention in daughter plates. The reaction is initiated by the addition of 20 µl of ATP (final concentration 200 µM). Rates of reaction are obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 minutes at 30 °C. The Ki values are determined from the rate data as a function of inhibitor concentration.
  • Table 11 depicts enzyme inhibition data (Ki) for certain exemplary compounds. Compound numbers in Table 11 corresponds to those compounds depicted in Table 5. In Table 11, "A" represents a Ki of less than 0.5 µM, "B" represents a Ki of between 0.5 and less than 5.0µM, and "C" represents a Ki of greater than or equal to 5.0 µM for the indicated enzyme.
  • Table 11: Biological Characterization Data for Selected Compounds
    Cmpd # (V-) AurA AurB ITK JAK3 Met RLK
    1 C
    2 B B C B
    3 B C B
    4 B C B
    5 B C B
    6 B B B
    7 B C B
    8 B C B
    9 B C B
    10 B C B
    11 B C B
    12 B C B
    13 B C B
    14 B B C B
    15 B C B
    16 B C B
    17 B C B
    18 A A C A
    19 B C B
    20 B C B
    21 B C B
    22 B B C A
    23 B C B
    24 B B C B
    25 B C B
    26 B C B
    27 B C B
    28 B C B
    29 B C B
    30 B C B
    31 B C B
    32 B C B
    33 B B C B
    34 B C B
    35 B C B
    36 B C B
    37 B C B
    38 B C B
    39 B C B
    40 B C B
    41 B C B
    42 B C B
    43 B C B
    44 B C B
    45 B C B
    46 B C B
    47 B C B
    48 B C B
    49 B C B
    50 B C A
    51 B A B A
    52 B C B
    53 B C A
    54 B B C A
    55 B B C A
    56 B C B
    57 B B C A
    58 B C A
    59 B C B
    60 B B A
    61 A B A
    62 B A B A
    63 A A B A
    64 A A B A
    65 B A B A
    66 B B A
    67 A B B A
    68 A A B A
    69 A B A
    70 A A B A
    71 A A B A
    72 A A B A
    73 B B C A
    74 B A B A
    75 A B C A
    76 A A B A
    77 B C B
    78 A A B A
    79 A A B A
    80 A C A
    81 A A B A
    82 B A C A
    83 A A B A
    84 A B A
    85 B A B A
    86 B B C A
    87 A A B A
    88 A B A
    89 A A B A
    90 A A B A
    91 A A A
    92 A A B A
    93 A A B A
    94 B A C A
    95 A B A
    96 B B C A
    97 A A B A
    98 A A B A
    99 A B A
    100 B C A
    101 B B C A
    102 B B C A
    103 B C A
    104 B B C A
    105 B C A
    106 B B C A
    107 B B A
    108 B C A
    109 B C A
    110 A B A
    111 B C A
    112 B B C A
    113 A B A
    114 B B C A
    115 B B C A
    116 B B C A
    117 B C A
    118 B C A
    119 B B A
    120 A B A
    121 B C A7
    122 A B A
    123 B C A
    124 B B C A
    125 B C A
    126 B C A
    127 B B C A
    128 B C A
    129 A A B A
    130 B A C A
    131 B B B
    132 B B B C A
    133 A B B B A
    134 B B B C B
    135 B B B C B
    136 B C B
    137 B C B
    138 B C B
    139 B B C A
    140 B C A
    141 B C A
    142 B B A
    143 B C
    144 B C A
    145 A C A
    146 B A C A
    147 B C B
    148 A B A
    149 B B A
    150 A C A
    151 B A C A
    152 B A C A
    153 A B A
    154 B B C A
    155 B A B A
    156 B B C A
    157 A C A
    158 B C A
    159 B A B A
    160 B B C A
    161 B C A
    162 B C B
    163 B C A
    164 A C A
    165 A A C A
    166 B A C A
    167 B C A
    168 B C B
    169 A C A
    170 B C B
    171 B C A
    172 B C B
    173 B A B A
    174 B C B
    175 B B B A
    176 B A B A
    177 A A B A
    178 A B A C B
    179 A A A A A
    180 A A A A
    181 A A A A
    182 A A A A
    183 A A B A
    184 A A B A
    185 A A A A
    186 A C B
    187 B C A
    188 A A B A A
    189 B A B A
    190 B A B A
    191 A A B A A
    192 A A
    193 A
    194 A A B A
    195 A A B A B
    196 A
    197 A C A
    198 B C B
    199 B C B
    200 B C B
    201 B C B
    202 B A C A B
    203 A
    204 B B C B
    205 B C B
    206 B B C B
    207 B C B
    208 A A B B
    209 A C B
    210 A
    211 B C B
    212 A A C A
    213 B C B
    214 A A B A B
    215 B A C A B
    216 B B C B
    217 A A B A A
    218 B
    219 B B C B
    220 B
    221 B B B A
    222 A A B A B
    223 B A B A B
    224 A A N A
    225 B B C A
    226 B A C A
    227 B A C A B
    228 B A C A B
    229 B A C A B
    230 A A B A A
    231 A A B A B
    232 B A C A B
    233 A A B A B
    234 A A B A B
    235 B C B
    236 A A B A B
    237 B A B A
    238 B B B A
    239 B C B
    240 B C B
    241 A A A A
    242 A A A A
    243 A A A A
    244 A A A A
    245 B C A
    246 B C A
    247 B C A
    248 B B A
    249 B B A
    250 A B A
    251 B C A
    252 B C B
    253 B C B
    254 B C B
    255 B C B
    256 B C B
    257 B C B
    258 B C B
    259 B C B
    260 B C B
    261 B C B
    262 B C B
    263 B C B
    264 B C B
    265 B C B
    266 B C B
    267 B C B
    268 B C B
    269 B C B
    270 B C B
    271 B C B
    272 B C B
    273 B B B B A
    274 B B A B A
    275 B C B
    276 B A B A
    277 B B B A
    278 B B B A
    279 A A A A
    280 A B C B
    281 B B B A
    282 B B A
    283 B B B
    284 B B A
    285 B B B A
    286 B B B A
    287 B B A
    288 A B A
    289 B B B A
    290 B B B A
    291 B B B A
    292 B B A
    293 B B B A
    294 B B B A
    295 B B B A
    296 A B A
    297 B B A
    298 A B A
    299 A A A
    300 B A A
    301 B C B
    302 A B A
    303 B B B
    304 B C B
    305 B C B
    306 B B A
    307 B B A
    308 A A A
    309 B A A
    310 B C B
    311 B C A
    312 B C B
    313 B C B
    314 B C B
    315 B C B
    316 B C B
    317 B C B
    318 B C B
    319 B C A
    320 B C B
    321 B C B
    322 B C B
    323 B C B
    324 B C A
    325 B C B
    326 B C B
    327 B C B
    328 B C B
    329 B C A
    330 B C B
    331 B C B
    332 A B A
    333 A B A
    334 B B A
    335 B B A
    336 B B A
    337 A A A
    338 B B A
    339 A A A
    340 B B A
    341 B B B
    342 B B A
    343 B B B
  • While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example above.

Claims (78)

  1. A compound of formula I':
    Figure imgb0235
     or a pharmaceutically accepted salt thereof, wherein
    R is -(C=Q)R2a, CN, or Y; wherein
    Y is a 5-10 membered monocyclic or bicyclic heterocyclyl, aryl, or heteroaryl ring; each Y is independently and optionally substituted with 0-5 JY;
    Q is O, NH, NR', or S;
    R' is C1-6alkyl optionally substituted with 0-4 occurrences of halo, C1-6aliphatic, NO2, NH2, -N(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1-6alkyl), OH, -O(C1-6alkyl), -C(O)(C1-6alkyl), -C(O)NH2, -C(O)N(C1-6alkyl), or -C(O)N(C1-6alkyl)2;
    R2a is C1-6aliphatic, C6-10aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, OR5, or N(R5)2; each R2a is independently and optionally substituted with 0-5 J2a;
    R1 is H, -C(O)(C1-6alkyl), -C(O)O(C1-6alkyl), -C(O)NH2, -C(O)N(C1-6alkyl), -C(O)N(C1- 6alkyl)2; or C1-6 aliphatic; each R1 is optionally substituted with 0-4 occurrences of halo, C1-6haloalkyl, C1-6aliphatic, NO2, NH2, -N(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1-6alkyl), OH, or -O(C1-6alkyl);
    Z is a bond or C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement;
    R3 and R4 are each independently H, halogen, C1-6 alkoxy, N(R5)2, CN, NO2, or Um-V wherein m is 0 or 1;
    V is H, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloaliphatic, 5-10 membered heterocyclyl, or C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement; V is optionally substituted with 0-4 R8;
    U is C1-12 alkylidene chain wherein up to two methylene units of the chain are optionally and independently replaced by -NH-, -NR5-, -O-, -S-, -CO2-, -OC(O)-, -C(O)CO-, -C(O)-, -C(O)NH-, -C(O)NR5-, -C(=N-CN), -NHCO-, -NR5CO-, -NHC(O)O-, -NR5C(O)O-, -SO2NH-, -SO2NR5-, -NHSO2-, -NR5SO2-, -NHC(O)NH-, -NR5C(O)NH-, -NHC(O)NR5-, -NR5C(O)NR5, -OC(O)NH-, -OC(O)NR5-, -NHNH-, -NHNR5-, -NR5NR5-, -NR5NH-, -NHSO2NH-, -NR5SO2NH-, -NHSO2NR5-, -NR5SO2NR5-, -SO-, -SO2-, -PO-, -PO2-, or -POR5-; U is optionally substituted with 0-6 JU;
    R5 is C1-4haloalkyl, -C(O)COR6, -C(O)R6, -C(O)OR6, -C(O)N(R6)2, -SO2R6, C0-6alkyl-heterocyclyl, C0-6alkyl-heteroaryl, C0-6alkyl-aryl, C0-6alkyl- cycloaliphatic or C1-6 aliphatic wherein up to three methylene unit of the aliphatic chain are optionally and independently replaced by -NR"-, -O-, -S-, -CO2-, - OC(O)-, -C(O)CO-, -C(O)-, -C(O)NR"-, -NR"CO-, -NR"C(O)O-, -SO2NR"-, -NR"SO2-, -C(O)NR"NR"-, -NR"C(O)NR"-, -OC(O)NR"-, -NR"NR"-, -NR"SO2NR"-, -SO-, -SO2-, -PO-, -PO2-, or -POR"- in a chemically stable arrangement; each R5 is independently and optionally substituted with 0-5 JR5; or two R5 groups taken together with the atom to which they are attached optionally join to form a 5-10 membered carbocyclic or heterocyclic ring; wherein said ring is optionally substituted with 0-4 J';
    R6 is H, C1-6alkoxy, C1-4haloalkyl, C0-6alkyl-heterocyclyl, C0-6alkyl-heteroaryl, C0-6alkyl- aryl, C0-6alkyl-cycloaliphatic, or C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement; each R6 is independently and optionally substituted with 0-5 JR6; or two R6 groups taken together with the atom to which they are attached optionally join to form a 5-10 membered carbocyclic or heterocyclic ring; wherein said ring is optionally substituted with 0-4 J";
    R8 is halogen, C1-4haloalkyl, phenyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, -OR6, -N(R6)2, -SR6, NO2, CN, -COOR6, -C(O)N(R6)2, -SO2R6, - SO2N(R6)2, -NR6C(O)R6, -C(O)R6, -OC(O)R6, -NR6C(O)O-R6, -NR6SO2-R6, -C(O)NR6N(R6)2, -NR6C(O)N(R6)2, -OC(O)N(R6)2, -NR6N(R6)2, -NR6SO2N(R6)2 or C1-12 aliphatic, wherein up to three methylene units of the aliphatic chain can be optionally interrupted with -C(O)R6, -C(O)O-, -OC(O)-, -C(O)-, -C(O)N(R6)-, -NR6CO(R6)-, -O-, -NR6-, or -S-; each R8 is independently and optionally substituted with 0-5 JR8;
    each JY, J2a, Ju, JR5, JR6, JR8, J', and J" is independently selected from N(R9)2, SR9, OR9, halo, CN, NO2, COOR9, C(O)R9, SO2R9, SOR9, -X-CF3, -X-SH, -X-OH, C1- 4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X;
    X is C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NH-, -NR"-, -O-, -S-, -CO2-, -OC(O)-, -C(O)CO-, -C(O)-, -C(O)NH-, -C(O)NR"-, -C(=N-CN), -NHCO-, -NR"CO-, -NHC(O)O-, -NR"C(O)O-, -SO2NH-, -SO2NR"-, -NHSO2-, -NR"SO2- -NHC(O)NH-, -NR"C(O)NH-, -NHC(O)NR"-, -NR"C(O)NR", -OC(O)NH-, -OC(O)NR"-, -NHNH-, -NHNR"-, -NR"NR"-, -NR"NH-, -NHSO2NH-, -NR"SO2NH-, -NHSO2NR"-, -NR"SO2NR"-, -SO-, -SO2-, -PO-, -PO2-, or -POR"-; in a chemically stable arrangement; wherein R" is H or C1-6 aliphatic;
    each JY, J2a, Ju, JR5, JR6, J', and J" is optionally and independently substituted with 0-4 occurrences of N(R9)2, SR9, OR9, halo, CN, NO2, COOR9, C(O)R9, SO2R9, SOR9, -X-CF3, -X-SH, -X-OH, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X;
    R9 is H, C1-6 aliphatic, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl) or X, or wherein two R9, taken together with the atom to which they are attached, form a 5-10 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 0-4 occurrences of halo, CN, NO2, -COOH, -COO(C1-6alkyl), - C(O)H, SO2H, SO2(C1-6alkyl), C1-6haloaliphatic, NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, SH, -S(C1-6alkyl), OH, -O(C1-6alkyl), -C(O)(C1-6alkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), -C(O)N(C1-6alkyl)2, -C(O)NH2, -C(O)NH(C1-6alkyl), or -C(O)N(C1-6alkyl)2, C1-4haloalkyl, C6-10 aryl, -X-(C6-10 aryl), 5-10 membered heteroaryl, -X-(5-10 membered heteroaryl), C3-10 cycloaliphatic, -X-(C3-10 cycloaliphatic), 5-10 membered heterocyclyl, -X-(5-10 membered heterocyclyl), or X, whereby the following compounds are excluded:
    - 3-(2-amino-5-methyl-pyrazolo[1,5-a]pyrimidine-3-yl)azo-4,6- dimethylthieno[2,3-b]pyridine,
    - 5-phenyl-3-phenylazo-pyrazolo[1,5-a]pyrimidin-2-ylamine.
  2. The compound according to claim 1, wherein R4 is H and R3 is other than H.
  3. The compound according to any one of claims 1-2, wherein Z is a bond.
  4. The compound according to any one of claims 1-3, wherein R1 is H.
  5. The compound according to any one of claims 1-2, wherein R is
    Figure imgb0236
  6. The compound according to claim 5, wherein Q is N or O.
  7. The compound according to claim 6, wherein Q is N.
  8. The compound according to claim 7, wherein Q is O.
  9. The compound according to any one of claims 5-8, wherein R2a is OR5, N(R5)2, or 5-8 membered heterocyclyl.
  10. The compound according to claim 9, wherein the 5-8 membered heterocyclyl contains 1-2 nitrogen atoms.
  11. The compound according to claim 10, wherein the 5-8 membered heterocyclyl is optionally substituted with 0-4 occurrences of C1-6aliphatic, C1-4haloalkyl, CN, halo, OH, O-(C1-6aliphatic), NH2, NH(C1-6aliphatic), N(C1-6aliphatic)2, benzyl, -CH2-(pyridyl), or -CH2-pyrrolidinyl.
  12. The compound according to claim 1, wherein R2a is N(R5)2.
  13. The compound according to claim 12, wherein R5 is H or an optionally substituted group selected from 5-8 membered heterocyclyl, -(C1-6alkyl)-(5-8 membered heterocyclyl), 5-6 membered heteroaryl -(C1-6alkyl)-(5-6 membered heteroaryl), phenyl, -(C1-6alkyl)-(phenyl), C3-10cycloaliphatic, -(C1-6alkyl)-(C3-10ocycloaliphatic) and C1-6 aliphatic wherein up to three methylene unit of the aliphatic chain are optionally and independently replaced by -NR"-, -O-, or -S- in a chemically stable arrangement.
  14. The compound according to claim 13, wherein R5 is H or an optionally substituted group selected from pyrrolidinyl, piperidinyl, piperazinyl, -CH2-(5-6 membered heteroaryl), phenyl, benzyl, and C1-6 aliphatic wherein up to one methylene unit of the aliphatic chain is optionally and independently replaced by -NR"-, -O-, or -S- in a chemically stable arrangement.
  15. The compound according to claim 14, wherein JR5 is halo, CN, C1-4haloalkyl, or an optionally substituted group selected from phenyl, benzyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, CH2-(5-6 membered heteroaryl), CH2-(5-8 membered heterocyclyl), and C1-6aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NR"-, -O-, -S-, -C(O)-, -SO-, or -SO2-, in a chemically stable arrangement.
  16. The compound according to claim 15, wherein JR5 is halo, CN, phenyl, benzyl, CH2-(pyridyl), CH2-(pyrrolidinyl), or C1-6aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NR"-, -O-, or -S-.
  17. The compound according to claim 1, wherein R is Y.
  18. The compound according to claim 17, wherein Y is an optionally substituted 5-10 membered heteroaryl.
  19. The compound according to claim 17, wherein Y is an optionally substituted 5-6 membered heteroaryl or 5-8 membered heterocyclyl.
  20. The compound according to claim 19, wherein Y is a pyridine ring optionally substituted with 0-4 JY.
  21. The compound according to claim 20, wherein Y is a 2-pyridine ring optionally substituted with 0-4 JY.
  22. The compound according to any one of claims 17-21, wherein JY is halo, CN, NO2, C1-6haloaliphatic, phenyl, benzyl, 5-6 membered heteroaryl, C1-6alkyl-(5-6 membered heteroaryl), C3-10 cycloaliphatic, (C1-6alkyl)-(C3-10 cycloaliphatic), 5-8 membered heterocyclyl, C1-6alkyl-(5-8 membered heterocyclyl), or C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NR-, -O-, -S-, -C(O)-, -SO-, or -SO2- in a chemically stable arrangement.
  23. The compound according to claim 22, wherein JY is halo, CN, NO2, CF3, C1-6 aliphatic, phenyl, benzyl, -O-benzyl, piperidinyl, pyrrolidinyl, -NR(C1-6alkyl), -O(C1-6alkyl), -S(C1-6alkyl), OH, SH, or NH2.
  24. The compound according to any one of claims 1-23, wherein R3 and R4 are each independently Um-V.
  25. The compound according to claim 24, wherein V is H, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloaliphatic, or 5-10 membered heterocyclyl optionally substituted with 0-4 R8.
  26. The compound according to claim 25, wherein V is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl, or 5-8 membered heterocyclyl.
  27. The compound according to claim 26, wherein V is an optionally substituted group selected from phenyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolidinyl, piperidinyl, or morpholinyl.
  28. The compound according to claim 27, wherein V is optionally substituted phenyl.
  29. The compound according to any one of claims 1-23, wherein R3 is Um-V; m is 1, and U is C1-6aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by -C(O)-, -C(O)NR5-, or -C(O)O-.
  30. The compound according to claim 29, wherein U is -C(O)NR5-.
  31. The compound according to claim 30, wherein V is optionally substituted phenyl or optionally substituted pyridyl.
  32. The compound according to any one of claims 1-28, wherein m is zero and V is aryl or heteroaryl.
  33. The compound according to any one of claims 1-32, wherein R8 is halogen, C1-4haloalkyl, phenyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, -OR6, -N(R6)2, -SR6, NO2, CN, -COOR6, -C(O)N(R6)2, -SO2R6, -SO2N(R6)2, -NR6C(O)R6, -C(O)R6, -NR6SO2-R6, -C(O)NR6N(R6)2, or C1-12 aliphatic, wherein up to three methylene units of the aliphatic chain can be optionally interrupted with -C(O)R6, -C(O)O-, -OC(O)-, -C(O)-, -C(O)N(R6)-, -NR6CO(R6)-, -O-, -NR6-, or -S-.
  34. The compound according to claim 33, wherein R8 is -OR6, -N(R6)2, C(O)R6, -C(O)N(R6)2, or 5-7 membered heterocyclyl.
  35. The compound according to claim 34, wherein R8 is -C(O)N(R6)2 or C(O)R6.
  36. The compound according to any one of claims 1-35, wherein R6 is H or an optionally substituted group selected from 5-8 membered heterocyclyl, -(C1-6alkyl)-(5-8 membered heterocyclyl), benzyl, -(C1-6alkyl)-(5-8 membered heteroaryl), and C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement.
  37. The compound according to claim 36, wherein R6 is H or an optionally substituted group selected from a 5-8 membered heterocyclyl and C1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement.
  38. The compound according to any one of claims 1-37, wherein JR6 is selected from C1-6alkyl, halo, CN, OH, -O(C1-6alkyl), NH2, -N(C1-6alkyl), and -N(C1-6alkyl)2.
  39. The compound according to any one of claims 1-38, wherein J" is selected from C1-6aliphatic, halo, CN, OH, -O(C1-6alkyl), NH2, -N(C1-6alkyl), -N(C1-6alkyl)2, -C(O)OH, -C(O)O(C1-6alkyl), 5-6 membered heteroaryl, -CH2-(5-6 membered heteroaryl), 5-6 membered heterocyclyl, -CH2-(5-6 membered heterocyclyl), and C1-6aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement.
  40. The compound according to claim 1, wherein Z is a bond and R is selected from
    Figure imgb0237
    Figure imgb0238
  41. The compound according to claim 40, wherein R is selected from
    Figure imgb0239
    Figure imgb0240
  42. The compound according to claim 41, wherein R is
    Figure imgb0241
  43. The compound according to any one of claims 40-42, wherein JY is selected from -X-(C6-10 aryl), -X-(5-10 membered heteroaryl), -X-(C3-10 cycloaliphatic), -X-(5-10 membered heterocyclyl), or X.
  44. The compound according to claim 43, wherein X is C1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by -NR"-, -O-, -S-, -C(O)-, -SO-, or -SO2-.
  45. The compound according to claim 44, wherein X is C1-12 aliphatic wherein up to one methylene unit is optionally and independently replaced by -NR"-.
  46. The compound according to either of claims 44 or 45, wherein at least one -NR"- is directly attached to R.
  47. The compound according to any one of claims 40-46, wherein JY is an optionally substituted group selected from C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloaliphatic, and 5-10 membered heterocyclyl.
  48. The compound according to any one of claims 40-46, wherein JY is halo, CN, NO2, CF3, OR", SR", or N(R")2.
  49. The compound according to any one of claims 40-46, wherein R is substituted with 2 occurrences of JY wherein one JY is selected from -X-(C6-10 aryl), -X-(5-10 membered heteroaryl), -X-(C3-10 cycloaliphatic), -X-(5-10 membered heterocyclyl), or X and the other JY is selected from H, halo, CN, NO2, CF3, OR", SR", N(R")2, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloaliphatic, or 5-10 membered heterocyclyl.
  50. The compound according to claim 49, wherein R is substituted with 2 occurrences of JY wherein one JY is selected from X and the other JY is selected from H, halo, CN, NO2, CF3, OR", SR", or N(R")2.
  51. The compound according to claim 1, wherein said compound is of formula II:
    Figure imgb0242
     or a pharmaceutically accepted salt thereof, wherein Ring A is Y.
  52. The compound according to claim 51, wherein R4 is H and R3 is other than H.
  53. The compound according to claim 52, wherein said compound is of formula III:
    Figure imgb0243
     or a pharmaceutically accepted salt thereof, wherein
    R3 is halogen, C1-6 aliphatic, C1-6 alkoxy, N(R5)2, CN, NO2, or Um-V;
    Ring A is a 5-8 membered monocyclic heteroaryl ring.
  54. The compound according to claim 53, wherein Ring A has the formula
    Figure imgb0244
  55. The compound according to claim 54, wherein Ring A has a formula selected from the group consisting of:
    Figure imgb0245
    Figure imgb0246
    Figure imgb0247
    Figure imgb0248
    Figure imgb0249
  56. The compound according to claim 55, wherein said compound is of formula IV:
    Figure imgb0250
     wherein each of Z1 and Z2 is CH or N.
  57. The compound according to claim 56, wherein Z2 is CH.
  58. The compound according to claim 57, wherein Z1 is N.
  59. The compound according to any of claims 51-58, wherein R3 is C1-6 aliphatic.
  60. The compound according to claim 59, wherein R3 is C1-3 alkyl.
  61. The compound according to claim 56, wherein JY is optionally substituted -N(R9)2.
  62. The compound according to claim 61, wherein JY is optionally substituted -NHR9.
  63. The compound according to claim 60, wherein JY is optionally substituted-N(R9)2, wherein said two R9 form a 5-8 membered heterocyclyl.
  64. A compound according to claim 1 selected from Table 5:
    Figure imgb0251
    Figure imgb0252
    Figure imgb0253
    Figure imgb0254
    Figure imgb0255
    Figure imgb0256
    Figure imgb0257
    Figure imgb0258
    Figure imgb0259
    Figure imgb0260
    Figure imgb0261
    Figure imgb0262
    Figure imgb0263
    Figure imgb0264
    Figure imgb0265
    Figure imgb0266
    Figure imgb0267
    Figure imgb0268
    Figure imgb0269
    Figure imgb0270
    Figure imgb0271
    Figure imgb0272
    Figure imgb0273
    Figure imgb0274
    Figure imgb0275
    Figure imgb0276
    Figure imgb0277
    Figure imgb0278
    Figure imgb0279
    Figure imgb0280
    Figure imgb0281
    Figure imgb0282
    Figure imgb0283
    Figure imgb0284
    Figure imgb0285
    Figure imgb0286
    Figure imgb0287
    Figure imgb0288
    Figure imgb0289
    Figure imgb0290
    Figure imgb0291
    Figure imgb0292
    Figure imgb0293
    Figure imgb0294
    Figure imgb0295
    Figure imgb0296
    Figure imgb0297
    Figure imgb0298
    Figure imgb0299
    Figure imgb0300
    Figure imgb0301
    Figure imgb0302
    Figure imgb0303
    Figure imgb0304
    Figure imgb0305
    Figure imgb0306
    Figure imgb0307
    Figure imgb0308
    Figure imgb0309
    Figure imgb0310
    Figure imgb0311
    Figure imgb0312
    Figure imgb0313
    Figure imgb0314
    Figure imgb0315
    Figure imgb0316
    Figure imgb0317
    Figure imgb0318
    Figure imgb0319
    Figure imgb0320
    Figure imgb0321
    Figure imgb0322
    Figure imgb0323
    Figure imgb0324
    Figure imgb0325
    Figure imgb0326
    Figure imgb0327
    Figure imgb0328
    Figure imgb0329
    Figure imgb0330
    Figure imgb0331
    Figure imgb0332
    Figure imgb0333
    Figure imgb0334
    Figure imgb0335
    Figure imgb0336
    Figure imgb0337
    Figure imgb0338
    Figure imgb0339
    Figure imgb0340
    Figure imgb0341
    Figure imgb0342
    Figure imgb0343
    Figure imgb0344
    Figure imgb0345
    Figure imgb0346
    Figure imgb0347
    Figure imgb0348
    Figure imgb0349
    Figure imgb0350
    Figure imgb0351
    Figure imgb0352
    Figure imgb0353
    Figure imgb0354
    Figure imgb0355
    Figure imgb0356
    Figure imgb0357
    Figure imgb0358
    Figure imgb0359
    Figure imgb0360
    Figure imgb0361
    Figure imgb0362
    Figure imgb0363
    Figure imgb0364
    Figure imgb0365
    Figure imgb0366
    Figure imgb0367
    Figure imgb0368
    Figure imgb0369
    Figure imgb0370
    Figure imgb0371
    Figure imgb0372
    Figure imgb0373
    Figure imgb0374
    Figure imgb0375
    Figure imgb0376
    Figure imgb0377
    Figure imgb0378
    Figure imgb0379
    Figure imgb0380
    Figure imgb0381
    Figure imgb0382
    Figure imgb0383
    Figure imgb0384
    Figure imgb0385
    Figure imgb0386
    Figure imgb0387
    Figure imgb0388
    Figure imgb0389
    Figure imgb0390
    Figure imgb0391
    Figure imgb0392
    Figure imgb0393
    Figure imgb0394
    Figure imgb0395
    Figure imgb0396
    Figure imgb0397
    Figure imgb0398
    Figure imgb0399
    Figure imgb0400
    Figure imgb0401
    Figure imgb0402
    Figure imgb0403
    Figure imgb0404
    Figure imgb0405
    Figure imgb0406
    Figure imgb0407
    Figure imgb0408
    Figure imgb0409
    Figure imgb0410
    Figure imgb0411
    Figure imgb0412
    Figure imgb0413
    Figure imgb0414
    Figure imgb0415
    Figure imgb0416
    Figure imgb0417
    Figure imgb0418
    Figure imgb0419
    Figure imgb0420
    Figure imgb0421
    Figure imgb0422
    Figure imgb0423
    Figure imgb0424
    Figure imgb0425
    Figure imgb0426
    Figure imgb0427
  65. A composition comprising a compound of any one of claims 1-64 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  66. The composition of claim 65, further comprising an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or an immunologically-mediated disease including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  67. A method of inhibiting Tec family kinase activity in vitro in a biological sample;
    which method comprises contacting said biological sample with a compound according to any one of claims 1-64 or a composition comprising said compound.
  68. The method according to claim 67, wherein the method comprises inhibiting Itk activity.
  69. The use of a composition comprising a compound according to any one of claims 1-64 in the manufacture of a medicament for treating or lessening the severity of a disease of condition selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease.
  70. The use according to claim 69, wherein the disease or disorder is asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease); Behcet's disease, Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata vernal conjunctivitis, Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies, multiple sclerosis, artherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following angioplasty, tumours, artherosclerosis, systemic lupus erythematosus, allograft rejection including, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
  71. The use of a compound according to any one of claims 1-64 or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of a cancer, preferably renal cancer, in a patient in need thereof.
  72. A method of inhibiting c-Met protein kinase activity in vitro in a biological sample comprising contacting said biological sample with a compound according to any one of claims 1-64 or a composition comprising said compound.
  73. The use of a compound according to any one of claims 1-64 or a composition comprising said compound in the manufacture of a medicament for treating or lessening the severity of a disease or condition selected from a glioblastoma, a gastric carcinoma or a cancer selected from colon, breast, prostate, brain, liver, pancreatic or lung cancer in a patient in need thereof.
  74. The use according to claim 73, wherein said disease or condition is gastric carcinoma.
  75. The use according to claim 73, wherein said disease or condition is glioblastoma or a cancer selected from breast, colon or liver.
  76. The use of a compound according to any one of claims 1-64 or a composition comprising said compound in the manufacture of a medicament for inhibiting tumor metastasis in a patient.
  77. The use of a compound according to any one of claims 1-64 or a composition comprising said compound in the manufacture of a medicament for treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof.
  78. A compound according to claim 1 selected from:
    Figure imgb0428
    Figure imgb0429
    Figure imgb0430
    Figure imgb0431
    Figure imgb0432
    Figure imgb0433
    Figure imgb0434
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Families Citing this family (102)

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Publication number Priority date Publication date Assignee Title
SE0104140D0 (en) * 2001-12-07 2001-12-07 Astrazeneca Ab Novel Compounds
ES2354824T3 (en) * 2004-11-04 2011-03-18 Vertex Pharmaceuticals, Inc. PIRAZOLO [1,5-A] USEFUL PYRIMIDINS AS INHIBITORS OF KINASE PROTEINS.
PT1853588E (en) * 2005-02-16 2008-08-25 Astrazeneca Ab Chemical compounds
WO2006124354A2 (en) * 2005-05-12 2006-11-23 Merck & Co., Inc. Tyrosine kinase inhibitors
KR20080015409A (en) * 2005-05-16 2008-02-19 아스트라제네카 아베 Chemical compounds
WO2007046867A2 (en) * 2005-05-19 2007-04-26 Xenon Pharmaceuticals Inc. Piperidine derivatives and their uses as therapeutic agents
CN101228161B (en) * 2005-05-20 2012-10-10 沃泰克斯药物股份有限公司 Pyrrolopyridines useful as inhibitors of protein kinase
EP1945631B8 (en) * 2005-10-28 2013-01-02 AstraZeneca AB 4- (3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer
PT3184526T (en) 2005-12-13 2018-12-19 Incyte Holdings Corp Pyrrolo[2,3-d]pyrimidine derivatives as janus kinase inhibitor
GB0601638D0 (en) * 2006-01-27 2006-03-08 Merck Sharp & Dohme Therapeutic treatment
US8198448B2 (en) 2006-07-14 2012-06-12 Amgen Inc. Fused heterocyclic derivatives and methods of use
PE20080403A1 (en) 2006-07-14 2008-04-25 Amgen Inc FUSED HETEROCYCLIC DERIVATIVES AND METHODS OF USE
US8217177B2 (en) 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
CA2668286C (en) * 2006-11-03 2014-09-16 Pharmacyclics, Inc. Bruton's tyrosine kinase activity probe and method of using
AU2008228768A1 (en) * 2007-03-22 2008-09-25 Vertex Pharmaceuticals Incorporated N-heterocyclic compounds useful as inhibitors of Janus Kinases
CN101679429A (en) * 2007-04-18 2010-03-24 阿斯利康(瑞典)有限公司 5-aminopyrazol-3-yl-3h-imidazo [4,5-b] pyridine derivatives and their use for the treatment of cancer
ES2369596T3 (en) * 2007-05-04 2011-12-02 Astrazeneca Ab DERIVATIVES OF AMINO-TIAZOLIL-PYRIMIDINE AND ITS USE FOR THE TREATMENT OF CANCER.
UA99459C2 (en) * 2007-05-04 2012-08-27 Астразенека Аб 9-(pyrazol-3-yl)- 9h-purine-2-amine and 3-(pyraz0l-3-yl)-3h-imidazo[4,5-b]pyridin-5-amine derivatives and their use for the treatment of cancer
US20080312259A1 (en) 2007-06-13 2008-12-18 Incyte Corporation SALTS OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE
JP5372763B2 (en) 2007-09-28 2013-12-18 協和発酵キリン株式会社 Preventive and / or therapeutic agent for skin diseases
EA020777B1 (en) * 2007-11-16 2015-01-30 Инсайт Корпорейшн 4-pyrazolyl-n-arylpyrimidin-2-amines, 4-pyrazolyl-n-pyrazolylpyrimidin-2-amines and 4-pyrazolyl-n-pyridylpyrimidin-2-amines as janus kinase inhibitors
PE20091268A1 (en) * 2007-12-19 2009-09-19 Amgen Inc HETEROCYCLIC DERIVATIVES AS PI3 KINASE INHIBITORS
CN101932583A (en) 2007-12-19 2010-12-29 沃泰克斯药物股份有限公司 Pyrazolo [1,5-a] pyrimidines useful as jak2 inhibitors
JP5638961B2 (en) 2008-03-13 2014-12-10 ザ ジェネラル ホスピタル コーポレイション Inhibitors of BMP signaling pathway
CA2727073A1 (en) * 2008-06-11 2009-12-17 Astrazeneca Ab Tricyclic 2,4-diamin0-l,3,5-triazine derivatives useful for the treatment of cancer and myeloproliferative disorders
US8394802B2 (en) * 2008-09-19 2013-03-12 Nerviano Medical Sciences S.R.L. 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one derivatives for the modulation of the activity of protein kinases
CN103965200B (en) 2008-09-22 2016-06-08 阵列生物制药公司 As imidazo [1,2-B] pyridazine compound of the replacement of TRK kinase inhibitor
RU2011116928A (en) * 2008-09-30 2012-11-20 Астразенека Аб (Se) HETEROCYCLIC INHIBITORS JAK KINASES
BRPI0914404A2 (en) * 2008-10-31 2019-03-06 Genentech Inc "compounds, pharmaceutical composition and method for treating or mitigating the severity of a disease or condition responsive to inhibition of jak kinase activity in a patient"
GB0821913D0 (en) 2008-12-02 2009-01-07 Price & Co Antibacterial compounds
ES2487542T3 (en) * 2009-05-22 2014-08-21 Incyte Corporation N- (hetero) aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo [2,3-d] pyrimidines and pyrrol-3-yl-pyrrolo [2,3-d] pyrimidines as Janus kinase inhibitors
CN106967070A (en) 2009-05-22 2017-07-21 因塞特控股公司 It is used as the compound of JAK inhibitor
WO2010138673A1 (en) * 2009-05-28 2010-12-02 Vertex Pharmaceuticals Incorporated Inhibitors of c-met protein kinase
GEP20156325B (en) 2009-06-17 2015-07-10 Vertex Pharma Inhibitors of influenza viruses replication
UA110324C2 (en) 2009-07-02 2015-12-25 Genentech Inc Jak inhibitory compounds based on pyrazolo pyrimidine
AR077468A1 (en) 2009-07-09 2011-08-31 Array Biopharma Inc PIRAZOLO COMPOUNDS (1,5-A) PYRIMIDINE SUBSTITUTED AS TRK-QUINASA INHIBITORS
AR078012A1 (en) * 2009-09-01 2011-10-05 Incyte Corp HETEROCICLIC DERIVATIVES OF PIRAZOL-4-IL-PIRROLO (2,3-D) PYRIMIDINS AS INHIBITORS OF THE QUANASA JANUS
JP5699149B2 (en) 2009-09-04 2015-04-08 バイオジェン・アイデック・エムエイ・インコーポレイテッド Bruton type tyrosine kinase inhibitor
TWI766281B (en) 2010-03-10 2022-06-01 美商英塞特控股公司 Piperidin-4-yl azetidine derivatives as jak1 inhibitors
US20130096160A1 (en) * 2010-04-14 2013-04-18 Secretary, Department Of Health And Human Services Arylthiazolyl piperidines and related compounds as modulators of survival motor neuron (smn) protein production
DK2571878T3 (en) 2010-05-17 2019-02-11 Indian Incozen Therapeutics Pvt Ltd Hitherto unknown 3,5-DISUBSTITUTED-3H-IMIDAZO [4,5-B] PYRIDINE AND 3,5- DISUBSTITUTED -3H- [1,2,3] TRIAZOL [4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF PROTEIN CHINES
KR102132405B1 (en) 2010-05-20 2020-07-09 어레이 바이오파마 인크. Macrocyclic compounds as trk kinase inhibitors
PE20130216A1 (en) 2010-05-21 2013-02-27 Incyte Corp TOPICAL FORMULATION FOR A JAK INHIBITOR
HUE028746T2 (en) 2010-06-01 2016-12-28 Summit Therapeutics Plc Compounds for the treatment of clostridium difficile associated disease
GB2480814A (en) * 2010-06-01 2011-12-07 Summit Corp Plc Compounds for the treatment of clostridium difficile-associated disease
AR083933A1 (en) 2010-11-19 2013-04-10 Incyte Corp PIRROLOPIRIDINE AND PIRROLOPIRIMIDINE DERIVATIVES REPLACED WITH CYCLOBUTILO AS JAK INHIBITORS
JP5917544B2 (en) 2010-11-19 2016-05-18 インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ Heterocyclic substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors
MX2013006836A (en) * 2010-12-16 2013-09-26 Vertex Pharma Inhibitors of influenza viruses replication.
EA031153B1 (en) * 2011-06-10 2018-11-30 Мерк Патент Гмбх Use of pyrimidine compounds with btk inhibitory activity
EA201490042A1 (en) 2011-06-20 2014-10-30 Инсайт Корпорейшн AZETIDINYL-PHENYL-, PYRIDYL- OR PYRAZYNYLKARBOXAMID DERIVATIVES AS INHIBITORS
EP2723746A1 (en) 2011-06-22 2014-04-30 Vertex Pharmaceuticals Inc. Compounds useful as inhibitors of atr kinase
UA118010C2 (en) 2011-08-01 2018-11-12 Вертекс Фармасьютікалз Інкорпорейтед INFLUENCES OF INFLUENZA VIRUS REPLICATION
TW201313721A (en) 2011-08-18 2013-04-01 Incyte Corp Cyclohexyl azetidine derivatives as JAK inhibitors
US9096605B2 (en) * 2011-08-24 2015-08-04 Glaxosmithkline Llc Pyrazolopyrimidine derivatives as PI3 kinase inhibitors
UA111854C2 (en) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн METHODS AND INTERMEDIATE COMPOUNDS FOR JAK INHIBITORS
SG11201406185WA (en) 2012-03-30 2014-11-27 Rhizen Pharmaceuticals Sa Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of c-met protein kinases
AR091079A1 (en) 2012-05-18 2014-12-30 Incyte Corp DERIVATIVES OF PIRROLOPIRIMIDINA AND PIRROLOPIRIDINA REPLACED WITH PIPERIDINILCICLOBUTILO AS JAK INHIBITORS
AR091273A1 (en) * 2012-06-08 2015-01-21 Biogen Idec Inc PYRIMIDINYL TIROSINE KINASE INHIBITORS
WO2014028829A1 (en) * 2012-08-16 2014-02-20 The Scripps Research Institute Novel kappa opioid ligands
SG11201503695XA (en) 2012-11-15 2015-06-29 Incyte Corp Sustained-release dosage forms of ruxolitinib
WO2014081996A1 (en) * 2012-11-23 2014-05-30 Glaxosmithkline Llc Novel compounds as diacylglycerol acyltransferase inhibitors
ES2946360T3 (en) 2012-12-07 2023-07-17 Vertex Pharma Pyrazolo[1,5-a]pyrimidines useful as ATR kinase inhibitors for the treatment of cancer diseases
TW201501713A (en) * 2013-03-01 2015-01-16 Kyowa Hakko Kirin Co Ltd Agent for preventing and/or treating ocular inflammatory disease
HUE057262T2 (en) 2013-03-06 2022-04-28 Incyte Holdings Corp Processes and intermediates for making a jak inhibitor
JP6542192B2 (en) 2013-03-14 2019-07-10 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドＴｈｅ Ｂｒｉｇｈａｍ ａｎｄ Ｗｏｍｅｎ’ｓ Ｈｏｓｐｉｔａｌ， Ｉｎｃ． BMP inhibitors and methods of use thereof
US8969360B2 (en) 2013-03-15 2015-03-03 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2014143241A1 (en) 2013-03-15 2014-09-18 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
WO2014143240A1 (en) 2013-03-15 2014-09-18 Vertex Pharmaceuticals Incorporated Fused pyrazolopyrimidine derivatives useful as inhibitors of atr kinase
WO2014175370A1 (en) * 2013-04-25 2014-10-30 塩野義製薬株式会社 Pyrrolidine derivative and pharmaceutical composition containing same
US9655854B2 (en) 2013-08-07 2017-05-23 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
EP3421468B1 (en) 2013-11-13 2020-11-04 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
RS59144B1 (en) 2013-11-13 2019-09-30 Vertex Pharma Inhibitors of influenza viruses replication
WO2015073267A1 (en) * 2013-11-15 2015-05-21 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
CN104650092B (en) * 2013-11-16 2017-11-10 广东东阳光药业有限公司 Substituted heteroaryl compound and combinations thereof and purposes
RU2687276C2 (en) 2013-12-06 2019-05-13 Вертекс Фармасьютикалз Инкорпорейтед Compounds suitable for use as atr kinase inhibitors
MX2016015062A (en) 2014-05-23 2017-02-27 Hoffmann La Roche 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds which are jak inhibitors.
US9498467B2 (en) 2014-05-30 2016-11-22 Incyte Corporation Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1
LT3152212T (en) 2014-06-05 2020-05-11 Vertex Pharmaceuticals Inc. Radiolabelled derivatives of a 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]- pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, the preparation of said compound and different solid forms thereof
SG11201610500WA (en) 2014-06-17 2017-01-27 Vertex Pharma Method for treating cancer using a combination of chk1 and atr inhibitors
US10513521B2 (en) 2014-07-15 2019-12-24 The Brigham And Women's Hospital, Inc. Compositions and methods for inhibiting BMP
RS64122B1 (en) 2014-11-16 2023-05-31 Array Biopharma Inc Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
WO2016183116A1 (en) 2015-05-13 2016-11-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
WO2016183120A1 (en) 2015-05-13 2016-11-17 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
CA3000684A1 (en) 2015-09-30 2017-04-06 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of dna damaging agents and atr inhibitors
BR112018008357A2 (en) 2015-10-26 2018-11-27 Array Biopharma Inc dot mutations in trk inhibitor resistant cancer and related methods
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
AU2017246554B2 (en) 2016-04-04 2022-08-18 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
HRP20230704T1 (en) 2016-05-18 2023-10-27 Loxo Oncology, Inc. Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
SI3484888T1 (en) 2016-07-18 2023-07-31 University Health Network Solid forms of ttk inhibitor
SG11201900515PA (en) 2016-07-21 2019-02-27 Biogen Ma Inc Succinate forms and compositions of bruton's tyrosine kinase inhibitors
JOP20190092A1 (en) 2016-10-26 2019-04-25 Array Biopharma Inc PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF
JOP20190213A1 (en) 2017-03-16 2019-09-16 Array Biopharma Inc Macrocyclic compounds as ros1 kinase inhibitors
EP3615538B1 (en) * 2017-04-27 2024-02-07 The Brigham and Women's Hospital, Inc. Novel alk2 inhibitors and methods for inhibiting bmp signaling
PL233595B1 (en) * 2017-05-12 2019-11-29 Celon Pharma Spolka Akcyjna Derivatives of pyrazolo[1,5-a]pyrimidine as inhibitors of kinase JAK
CR20190520A (en) 2017-05-22 2020-01-21 Hoffmann La Roche Therapeutic compounds and compositions, and methods of use thereof
AR113922A1 (en) 2017-12-08 2020-07-01 Incyte Corp LOW DOSE COMBINATION THERAPY FOR THE TREATMENT OF MYELOPROLIFERATIVE NEOPLASMS
US10988477B2 (en) * 2018-01-29 2021-04-27 Merck Patent Gmbh GCN2 inhibitors and uses thereof
CN112105608B (en) 2018-01-30 2023-07-14 因赛特公司 Process for the preparation of (1- (3-fluoro-2- (trifluoromethyl) isonicotinyl) piperidin-4-one
AU2019245420A1 (en) 2018-03-30 2020-11-12 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
JP7504880B2 (en) 2018-10-26 2024-06-24 ケロス セラピューティクス インコーポレイテッド Crystalline forms of ALK2 inhibitors
KR20210116488A (en) 2018-12-20 2021-09-27 인사이트 코포레이션 Imidazopyridazine and imidazopyridine compounds as inhibitors of activin receptor-like kinase-2
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2291709A1 (en) * 1997-05-30 1998-12-03 Merck & Co., Inc. Novel angiogenesis inhibitors
US6245759B1 (en) * 1999-03-11 2001-06-12 Merck & Co., Inc. Tyrosine kinase inhibitors
GB0103926D0 (en) * 2001-02-17 2001-04-04 Astrazeneca Ab Chemical compounds
US7550470B2 (en) 2002-12-11 2009-06-23 Merck & Co. Inc. Substituted pyrazolo[1,5-A]pyrimidines as tyrosine kinase inhibitors
ES2354824T3 (en) * 2004-11-04 2011-03-18 Vertex Pharmaceuticals, Inc. PIRAZOLO [1,5-A] USEFUL PYRIMIDINS AS INHIBITORS OF KINASE PROTEINS.

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